Osteoclasts and Microgravity
Open accessPublished version of a preprint
Abstract
Astronauts are at risk of losing 1.0% to 1.5% of their bone mass for every month they spend in space despite their adherence to diets and exercise regimens designed to protect their musculoskeletal systems. This loss is the result of microgravity-related impairment of osteocyte and osteoblast function and the consequent upregulation of osteoclast-mediated bone resorption. This review describes the ontogeny of osteoclast hematopoietic stem cells and the contributions macrophage colony stimulating factor, receptor activator of the nuclear factor-kappa B ligand, and the calcineurin pathways make in osteoclast differentiation and provides details of bone formation, the osteoclast cytoskeleton, the immune regulation of osteoclasts, and osteoclast mechanotransduction on Earth, in space, and under conditions of simulated microgravity. The article discusses the need to better understand how osteoclasts are able to function in zero gravity and reviews current and prospective therapies that may be used to treat osteoclast-mediated bone disease.
AI snapshot
Written from the paper’s full text.
TL;DR
This narrative review argues that microgravity impairs osteocyte and osteoblast function while osteoclast-mediated bone resorption remains active or increases, contributing to spaceflight bone loss. It reviews osteoclast ontogeny, cytoskeleton, immune regulation, mechanotransduction, and candidate therapies for osteoclast-mediated bone disease.
Key findings
- Astronauts are at risk of losing 1.0%–1.5% of bone mass per month in space, and space-related bone and joint changes may persist for years after return to Earth.
- In spaceflight animal studies, 7-day BIOCOSMOS 1667 rats showed reduced tibial trabecular bone volume by 47–55%, trabecular thickness by 20–24%, and trabecular density by 40–43%, while femoral insertion sites and vertebrae showed no significant changes; 15-day STS-131 mice showed 6.3% lower bone volume, 11.9% lower bone thickness, and 170% more bone-surface TRAP-positive osteoclasts.
- Cell and animal studies report increased osteoclast resorption under microgravity: approximately 16,000 resorptive pits on Osteologic slides after 5 days of spaceflight, several-fold increased osteoclast activation/function genes and collagen telopeptide after 10 days on FOTON-M3, and a twofold increase in osteoclastogenesis in simulated microgravity RAW 264.7 cultures.
- Therapies discussed include bisphosphonates, denosumab, odanacatib, romosozumab, osteoprotegerin-Fc, melatonin, and IGF-1; IGF-1 increased rodent humerus periosteal bone formation by 37% during a 10-day Space Shuttle flight.
Methods
- Narrative review of microgravity effects on osteoclast ontogeny and function, using a PubMed search with defined key topics and keywords, refined based on initial findings.
- Data restrictions included articles with identical samples and identical outcomes, identical samples with different outcomes, increased samples and identical outcomes, and decreased samples with identical outcomes.
- No primary experiments or meta-analysis are described; evidence is synthesized from cited animal, cell culture, spaceflight, and simulated-microgravity studies.
Limitations
- The paper does not state formal limitations.
- Evident from the text: it is a narrative review, not a systematic review or meta-analysis, and no formal risk-of-bias assessment or quantitative pooling is described.
- Evident from the text: conclusions rely on heterogeneous species and models (rats, mice, medaka fish, cell cultures) and varied microgravity platforms, which may limit generalizability.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
75 of 154 cited sources checked · 24 supported · 4 flagged · accuracy not yet measured
- Premisecitation
Bone marrow osteoclast hematopoietic stem cells expressing S1PR2 enter the circulation by binding S1P, a chemotactic lysophospholipid normally present in high concentrations in blood.
“Bone marrow osteoclast hematopoietic stem cells (HSCs) expressing type-2 receptor for sphingosine-1-phosphate (S1PR2) enter the circulation by binding sphingosine-1-phosphate (S1P), a chemotactic lysophospholipid normally present in high concentrations in blood [15,16].”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [15] Ishii, 2009, Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis, Nature source
The paper’s Abstract supports S1P-driven recirculation of osteoclast precursors toward blood, where S1P levels are high. But it identifies the migrating cells as monocyte-lineage precursors, not hematopoietic stem cells, and attributes the demonstrated recirculation mechanism to S1P1 rather than S1PR2; it reports S1P2 mRNA expression without establishing that mechanism for S1P2. No page number is available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [16] Ishii, 2011, The role of sphingosine 1-phosphjate in migration of osteoclast precursors; an application of intravital two-photon microscopy, Mol. Cells source
The “Osteoclast precursors and S1P” section (page not provided) says S1PR2 activation moves osteoclast precursors from the bloodstream into bone marrow, the opposite of the claimed direction. The intravital-imaging section attributes their movement toward blood vessels to S1PR1-mediated chemotaxis. The paper does support that S1P is abundant in blood, but describes the precursors as macrophage/monocyte-lineage cells rather than hematopoietic stem cells. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Premisecitation
IL-18 inhibits osteoclastogenesis by downregulating osteoblast production of M-CSF.
“Using co-cultures of osteoblasts and hematopoietic cells, Udagawa and associates found that IL-18 inhibited osteoclastogenesis by downregulating osteoblast production of M-CSF [48].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [48] Udagawa, 1997, Interleukin-18 (interferon-gamma-inducing-factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-gamma to inhibit osteoclast formation, J. Exp. Med. source
The Results section, “IL-18 Inhibits OCL Formation Via GM–CSF” (page unavailable), attributes the inhibition to increased production of GM–CSF. It does not identify downregulation of osteoblast M-CSF production as the mechanism; M-CSF and GM–CSF are different factors. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Premisecitation
In the STS-131 mouse study, osteocyte apoptosis was documented as reflected by increases in lacunar and canalicular diameters.
“They also documented osteocyte apoptosis as reflected by increases in lacunar and canalicular diameters [60].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [60] Blaber, E.A., Dvorochkin, N., Lee, C., Alwood, J.S., Yousuf, R., Pianetta, P., Globus, R.K., Burns, B.P., and Almeida, E.A. (2013). Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21. PLoS ONE, 8. source
The Results report enlarged lacunae and increased canalicular diameter after spaceflight, but interpret these as signs of osteocytic osteolysis, not apoptosis. In the same Results section, empty-lacuna counts did not differ between flight and ground mice, and pyknotic nuclei were not detected in osteocytes; the Discussion likewise reports no apparent difference in cell death. No page numbers are available in our copy. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Premisecitation
Conditions of microgravity and simulated microgravity increase osteoclast secretion of sclerostin.
“increase osteoclast secretion of sclerostin”
Quote in the paperSubstantial claim4 of 10 sources checked- cites [57] Vico, 1988, Trabecular bone remodeling after seven days of weightlessness exposure (BIOCOSMOS 1667), Am. J. Physiol. source
- cites [58] Vico, 1987, Effects of weightlessness on bone mass and osteoclast number in pregnant rats after a five-day spaceflight (COSMOS 1514), Bone source
- cites [59] Vico, 1985, Histomorphometric analysis of cancellous bone from COSMOS 2044 rats, J. Appl. Physiol. source
- cites [60] Blaber, E.A., Dvorochkin, N., Lee, C., Alwood, J.S., Yousuf, R., Pianetta, P., Globus, R.K., Burns, B.P., and Almeida, E.A. (2013). Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21. PLoS ONE, 8. source
The Abstract reports increased osteoclast-covered bone surfaces after spaceflight, and the Discussion describes secretion of MMPs by osteoclasts. Neither passage addresses osteoclast secretion of sclerostin; searches for sclerostin and SOST also found no passage supporting the claim for either microgravity or simulated microgravity. (LLM, conf=0.72)
Experimental — accuracy not yet measured - cites [61] Chatani, 2016, Acute transcriptional up-regulation specific to osteoblasts/osteoclasts in medaka fish immediately after exposure to microgravity, Sci. Rep. source
The Discussion reports increased osteoclast signals and expression of osteoclast-related genes in medaka exposed to actual microgravity. It does not report osteoclast secretion of sclerostin or establish that simulated microgravity has that effect; the Discussion distinguishes this study from earlier work using artificial microgravity. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [62] Tamma, 2009, Microgravity during spaceflight directly affects in vitro osteoclastogenesis and bone resorption, FASEB J. source
- cites [63] Saxena, 2011, Modeled microgravity and hindlimb unloading sensitize osteoclast precursors to RANKL-mediated osteoclastogenesis, J. Bone Miner. Metab. source
The Discussion attributes increased sclerostin secretion during unloading to osteocytes, not osteoclasts. It describes the paper’s own finding as an increased response of osteoclast precursors to modeled microgravity, without reporting increased sclerostin secretion by osteoclasts. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [64] Aguirre, 2006, Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss, J. Bone Miner. Res. source
- cites [65] Rucci, 2007, Modeled microgravity stimulates osteoclastogenesis and bone resorption by increasing osteoblast RANKL/OPG ratio, J. Cell. Biochem. source
The Discussion reports that modeled microgravity changed osteoblast release of OPG and RANKL, stimulating osteoclast differentiation and activity. Neither the provided passages nor searches for sclerostin and SOST address whether microgravity increases osteoclast secretion of sclerostin. (LLM, conf=0.77)
Experimental — accuracy not yet measured - cites [66] Sambandam, 2010, Microarray profile of gene expression during osteoclast differentiation in modelled microgravity, J. Cell. Biochem. source
- Premisecitation
Space travel has adverse effects on the osteoimmunological system, particularly bone homeostasis.
“Man’s venture into the vacuum of space where the force of gravity is one millionth of that on Earth has resulted in adverse effects on the osteoimmunological system, particularly bone homeostasis [8].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] Smith, J.K. (2020). Microgravity, bone homeostasis, and insulin-like growth factor-1. Appl. Sci., 10. source
The Introduction says microgravity adversely affects the musculoskeletal system, particularly bone, and §3.2 reports bone loss in astronauts after spaceflight. The IGF-1 section also describes gravity in space as one-millionth of that on Earth. The source does not establish the broader claim about adverse effects on the osteoimmunological system; it refers instead to the musculoskeletal system. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Space-related bone and joint changes may persist for years after astronauts return to Earth despite efforts to protect their skeletal systems.
“Astronauts are not only at risk of progressive bone and cartilage loss while in space but must also face the reality that space-related bone and joint changes may persist for years after their return to Earth despite efforts made to protect their skeletal systems [8,9,10,11,12,13].”
Quote in the paperNot a substantial claim3 of 6 sources checked- cites [8] Smith, J.K. (2020). Microgravity, bone homeostasis, and insulin-like growth factor-1. Appl. Sci., 10. source
The Osteoblasts section reports bone loss in astronauts during spaceflight, and the Discussion describes efforts to find treatments for it. Neither passage establishes that bone or joint changes persist for years after astronauts return to Earth; the copy passages found do not address that duration or post-flight joint changes. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [9] Iwamoto, 2005, Interventions to prevent bone loss in astronauts during space flight, Keio J. Med. source
The Introduction (page unavailable) says osteoporosis after space flight may increase fracture risk in later life, and the Conclusions discuss limited evidence for interventions to prevent bone loss. The paper does not establish that bone changes persist for years after return despite protective efforts, and it does not address persistent joint or cartilage changes. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [10] Cavanagh, 2005, Exercise and pharmacological countermeasures for bone loss during long-duration space flight, Gravit. Space Biol. Bull.
Not checked in the free run.
- cites [11] Smith, 2012, Space flight calcium: Implications for astronaut health, spaceflight operations, and Earth, Nutrients source
Section 2 (Bone Loss) documents bone loss during space flight, and Section 6 (Bone Loss Countermeasures) discusses efforts to prevent it. Neither passage establishes that bone or joint changes persist for years after astronauts return to Earth; the paper also reports that some nutrition and exercise regimens maintained bone mineral density during flight. No page numbers were available in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [12] Leblanc, 2013, Biphosphonates as a supplement to exercise to protect bone during long-duration spaceflight, Osteoporos. Int. source
- cites [13] (2020, June 12). NASA—Food for Space Flight, Available online: https:/www.nasa.gov/specials/apollo50thy/index.html.
Not checked in the free run.
- Premisecitation
Astronauts are at risk of progressive bone and cartilage loss while in space.
“Astronauts are not only at risk of progressive bone and cartilage loss while in space but must also face the reality that space-related bone and joint changes may persist for years after their return to Earth despite efforts made to protect their skeletal systems [8,9,10,11,12,13].”
Quote in the paperSubstantial claim3 of 6 sources checked- cites [8] Smith, J.K. (2020). Microgravity, bone homeostasis, and insulin-like growth factor-1. Appl. Sci., 10. source
Section 3.2 (Osteoblasts; page unavailable) reports bone loss in astronauts after a month of spaceflight, supporting the bone-loss portion. The passages retrieved for cartilage loss do not address cartilage, so this source does not support that portion of the attributed claim. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [9] Iwamoto, 2005, Interventions to prevent bone loss in astronauts during space flight, Keio J. Med. source
The Introduction reports progressive bone loss during space flight, including monthly decreases in bone mineral density. Our copy does not report cartilage loss, so the cited paper supports only the bone-loss portion of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [10] Cavanagh, 2005, Exercise and pharmacological countermeasures for bone loss during long-duration space flight, Gravit. Space Biol. Bull.
Not checked in the free run.
- cites [11] Smith, 2012, Space flight calcium: Implications for astronaut health, spaceflight operations, and Earth, Nutrients source
Section 2, “Bone Loss” (page not supplied), reports that astronauts and cosmonauts generally lost 1.0%–1.5% of bone mineral density per month of space flight. The passages found do not address cartilage loss, so the source supports only the bone-loss part of the claim. Section 6 also notes that nutrition and resistance exercise can maintain bone mineral density during flight. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [12] Leblanc, 2013, Biphosphonates as a supplement to exercise to protect bone during long-duration spaceflight, Osteoporos. Int. source
- cites [13] (2020, June 12). NASA—Food for Space Flight, Available online: https:/www.nasa.gov/specials/apollo50thy/index.html.
Not checked in the free run.
- Premisecitation
M-CSF ligation initiates expression of several cytokines and receptors and factors involved in the cell's response to RANKL ligation.
“M-CSF ligation also initiates the expression of several cytokines and their receptors including interleukin (IL)-1α, IL-18, interferon (IFN)-β, IL-11Rα2, IL-6/11R gp130, and IFN-γ-R; also expressed are factors involved in the cell’s response to RANKL ligation, including tumor necrosis factor receptor-associated factor 2A (TRAF2A), phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein Kin”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [19] Cappellen, 2002, Transcriptional program of mouse osteoclast differentiation governed by the macrophage colony-stimulating factor and the ligand for receptor activator of NFkB, J. Biol. Chem. source
- Premisecitation
CXCR4+ CD45− cells support an appropriate microenvironment for osteoclastogenesis, with a direct effect on cells expressing SDF-1, CXCL7, and CX3CL1 receptors.
“Their findings suggest that CXCR4+ CD45− cells support an appropriate microenvironment for osteoclastogenesis, with a direct effect on cells expressing SDF-1, CXCL7, and CX3CL1 receptors [14].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] Goto, 2016, CXCR4+ CD45− cells are niche forming for osteoclastogenesis via the SDF-1, CXCL7, and CX3CL1 signaling pathways in bone marrow, Stem Cells source
The Conclusion says CXCR4+ CD45− cells may form a niche that supports osteoclastogenesis, and the Discussion reports their release of SDF-1, CXCL7, and CX3CL1. The SDF-1/CXCR4 Signaling for OC Formation section reports effects of blocking these chemokines on osteoclast formation, but does not establish a direct effect of the CXCR4+ CD45− cells on cells shown to express all three corresponding receptors. No page numbers are available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Premisecitation
Circulating CXCR4-expressing HSCs are attracted to bone surfaces by gradients of SDF-1 (CXCL12) secreted by CXCR4+ CD45−, stromal, and endothelial marrow cells.
“Circulating CXCR4-expressing HSCs are attracted to bone surfaces by gradients of SDF-1 (CXCL12) secreted by CXCR4+ CD45−, stromal, and endothelial marrow cells [14,17].”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [14] Goto, 2016, CXCR4+ CD45− cells are niche forming for osteoclastogenesis via the SDF-1, CXCL7, and CX3CL1 signaling pathways in bone marrow, Stem Cells source
The Introduction says bone-marrow stromal cells secrete SDF-1 and attract CXCR4-positive cells along its concentration gradient. The section on chemokine expression reports SDF-1 in CXCR4-positive CD45-negative cells. Neither passage establishes that the attracted cells are circulating HSCs, that they move to bone surfaces, or that endothelial marrow cells secrete SDF-1. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [17] Tamura, 2011, Regulation of CXCL12 expression by canonical Wnt signaling in bone marrow stromal cells, Int. J. Biochem. Cell Biol. source
The Introduction says marrow stromal and endothelial cells produce CXCL12, HSCs express its receptor CXCR4, and CXCL12–CXCR4 interactions help maintain HSC niches on bone’s endosteal surface. The Discussion describes CXCL12 as a chemoattractant. Neither section identifies CXCR4+ CD45− cells as CXCL12 producers or establishes that gradients attract circulating HSCs toward bone surfaces. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
NFATc1 binds to its own promoter, switching on an epigenetically controlled autoregulatory cycle that permits efficient induction of TRAP, cathepsin K, DC-STAMP, and ATP6v0d2.
“NFATc1 binds to its own promoter, switching on an epigenetically controlled autoregulatory cycle that permits efficient induction of the osteoclast-specific genes, tartrate-resistant acid phosphatase (TRAP), cathepsin K, as well as the fusion-specific genes, dendritic cell-specific transmembrane protein (DC-STAMP) and ATPase H+ transporting V0 subunit D2 (ATP6v0d2) [20,25,26] (Figure 3).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [20] Kim, 2014, Regulation of NFATc1 in osteoclast differentiation, J. Bone Metab. source
The 'Transcriptional regulation of NFATc1 in osteoclasts' section (page not provided) reports recruitment of NFATc1 to its own promoter and an epigenetically supported autoregulatory loop. The Introduction (page not provided) identifies TRAP and cathepsin K as NFATc1-regulated genes, but our copy does not identify DC-STAMP or ATP6v0d2 as targets or establish that the loop permits induction of all four genes. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [25] Takayanagi, 2007, The role of NFAT in osteoclast formation, Ann. N. Y. Acad. Sci. source
- cites [26] Asagiri, 2007, The molecular understanding of osteoclast differentiation, Bone source
- Premisecitation
A small population of CXCR4+ CD45− bone marrow cells provides a niche for osteoclastogenesis.
“Goto and associates have provided evidence that a small population of cysteine x cysteine receptor 4+ cluster of differentiation 45− (CXCR4+ CD45−) bone marrow cells provide a niche for osteoclastogenesis.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] Goto, 2016, CXCR4+ CD45− cells are niche forming for osteoclastogenesis via the SDF-1, CXCL7, and CX3CL1 signaling pathways in bone marrow, Stem Cells source
- Premisecitation
In addition to gravity, mechanotransduction in bone is mediated by fluid shear stresses, hydrostatic pressures, and the force of muscular contraction.
“In addition to the force of gravity, mechanotransduction in bone is mediated by fluid shear stresses [50], hydrostatic pressures [51], and the force of muscular contraction [52].”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [50] Hillsley, 1994, Bone tissue engineering: Role of interstitial fluid flow, Biotechnol. Bioeng. source
- cites [51] Liu, 2010, Effects of cyclic hydraulic pressure on osteocytes, Bone source
- cites [52] Smith, 2018, IL-6 and the dysregulation of immune, bone, muscle, and metabolic homeostasis during spaceflight, NPJ Microgravity source
Citation [52] is attached to the claim that muscular contraction mediates mechanotransduction in bone. The ‘IL-6 and bone homeostasis > In Space’ section says osteocytes transduce bone-loading signals, and the Introduction discusses exercise-related bone changes, but neither identifies muscular contraction as the source of those signals. Searches for ‘force of muscular contraction,’ ‘muscle contractions mechanical loading,’ and ‘contraction’ found no passage making that link. (LLM, conf=0.73)
Experimental — accuracy not yet measured
- Premisecitation
TNF-α has the capacity to inhibit osteoblastogenesis by downregulating expression of IGF-1 in mesenchymal stem cell precursors.
“In addition, TNF-α has the capacity to inhibit osteoblastogenesis by downregulating the expression of IGF-1 in mesenchymal stem cell precursors [32].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [32] Gilbert, 2000, Inhibition of osteoblast differentiation by tumor necrosis factor-alpha, Endocrinology source
The Abstract reports that TNF-α inhibits differentiation of fetal calvaria precursor cells and reduces IGF-I expression. But the Discussion says added IGF-I does not overcome the inhibition and places TNF-α’s action downstream of IGF-I; it does not support downregulation of IGF-I as the mechanism. The experiments used fetal calvaria precursors and a clonal osteoblastic cell line, not specifically identified mesenchymal stem cells. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Premisecitation
IL-4 inhibits osteoclastogenesis by blocking the JNK, p38, and ERK protein kinase pathways, which are upstream of NFATc1.
“Wei and associates found that IL-4 inhibited osteoclastogenesis by blocking the JNK, p38, and ERK protein kinase pathways, which are upstream of NFATc1 [40].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [40] Wei, 2002, Interleukin-4 reversibly inhibits osteoclastogenesis via inhibition of NF-kappa B and mitogen-activated protein kinase signaling, J. Biol. Chem. source
The Abstract and Discussion report that IL-4 inhibits osteoclastogenesis and, after prolonged treatment, blocks RANKL-induced JNK, p38, and ERK activation. The cited paper does not identify these pathways as upstream of NFATc1; a search for NFATc1 found no passage establishing that relationship. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
IL-4 limits bone resorption by promoting OPG expression and suppressing expression of RANKL, RANK, NF-κB, c-Fos, NFATc1, MAPK, and calcium signaling during osteoclast formation.
“Furthermore, Zhao and Ivashkiv reported that IL-4 limits bone resorption by promoting OPG expression and suppressing the expression of RANKL, RANK, NF-κB, c-Fos, NFATc1, MAPK, and calcium signaling during osteoclast formation [42].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [42] Zhao, 2011, Negative regulation of osteoclastogenesis and bone resorption by cytokines and transcriptional repressors, Arthritis Res. Ther. source
- Premisecitation
IL-10 limits osteoclast formation by inhibiting expression of c-Fos, c-Jun, TREM2, and NFATc1 in osteoclast precursors.
“Additionally, Zhao and Ivashkiv reported that IL-10 limits osteoclast formation by inhibiting the expression of c-Fos, c-Jun, TREM2, and NFATc1 in osteoclast precursors [42].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [42] Zhao, 2011, Negative regulation of osteoclastogenesis and bone resorption by cytokines and transcriptional repressors, Arthritis Res. Ther. source
- Premisecitation
IL-6 and its soluble receptor sIL-6r suppress differentiation of osteoclasts by inducing chondrocytic PGE2.
“He found that IL-6 and IL-6r suppressed the differentiation of osteoclasts by inducing chondrocytic PGE2 [44].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [44] Honda, 2011, Interleukin-6 and soluble interleukin-6 receptor suppress osteoclast differentiation by inducing PGE(2) production in chondrocytes, J. Oral Sci. source
The Discussion concludes that IL-6 and sIL-6r may suppress osteoclast differentiation through PGE2 production in chondrocytes. The citing sentence presents this proposed causal mechanism as an established finding, whereas the paper frames it as a conclusion suggested by its results. (LLM, conf=0.78)
Experimental — accuracy not yet measured
- Premisecitation
Microgravity produced multiple autophagosomes in RAW 264.7 cultures.
“produced multiple autophagosomes in RAW 264.7 cultures”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [67] Sambandam, 2014, Microgravity control of autophagy modulates osteoclastogenesis, Bone source
- Rests on an assumption: Simulated microgravity using the RWV is a valid model for actual microgravity conditions in space.
- Premisecitation
Expression of TRAIL, TRAF-6, and fusion genes OC-STAMP and DC-STAMP were upregulated in simulated microgravity in RAW 264.7 osteoclast precursors.
“the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAF-6, and the fusion genes OC-STAMP and DC-STAMP were upregulated in simulated microgravity”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [68] Sambandam, 2016, Microgravity induction of TRAIL expression in preosteoclast cells enhances osteoclast differentiation, Sci. Rep. source
The Results section on TRAIL expression reports upregulation in RAW 264.7 cells under simulated microgravity. The Results section on TRAF6 and fusion genes reports increased TRAF6, OC-STAMP, and DC-STAMP in mouse bone-marrow-derived preosteoclast cells, not specifically in RAW 264.7 cells. The claimed cell type is therefore supported for TRAIL but not for all four markers; page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Rests on an assumption: Simulated microgravity using the RWV is a valid model for actual microgravity conditions in space.
- Premisecitation
3-MA inhibition of autophagy in RANKL/CSF+ marrow cultures inhibited osteoclastogenesis.
“3-MA inhibition of autophagy in the RANKL/CSF+ marrow cultures inhibited osteoclastogenesis”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [67] Sambandam, 2014, Microgravity control of autophagy modulates osteoclastogenesis, Bone source
- Rests on an assumption: Simulated microgravity using the RWV is a valid model for actual microgravity conditions in space.
- Premisecitation
Autophagy plays an important role in enhanced osteoclast differentiation.
“autophagy plays an important role in enhanced osteoclast differentiation”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [67] Sambandam, 2014, Microgravity control of autophagy modulates osteoclastogenesis, Bone source
- Rests on an assumption: Simulated microgravity using the RWV is a valid model for actual microgravity conditions in space.
- Premisecitation
Microgravity increased the expression of autophagic genes in RAW 264.7 cultures.
“microgravity increased the expression of autophagic genes”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [67] Sambandam, 2014, Microgravity control of autophagy modulates osteoclastogenesis, Bone source
- Rests on an assumption: Simulated microgravity using the RWV is a valid model for actual microgravity conditions in space.
- Premisecitation
There is some concern about the potential cardiotoxicity of romosozumab.
“there is some concern about the potential cardiotoxicity of romosozumab”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [74] Shakeri, 2020, Romosozumab (sclerostin monoclonal antibody) for the treatment of osteoporosis in postmenopausal women: A review, J. Popul. Ther. Clin. Pharmacol. source
- Premisecitation
In experimental animals, sclerostin generated in response to TNF-α and IL-1β improves post-traumatic osteoarthritis by inhibiting the activity of proteolytic enzymes involved in cartilage degradation.
“sclerostin generated in response to TNF-α and IL-1β improves post-traumatic osteoarthritis by inhibiting the activity of proteolytic enzymes involved in cartilage degradation [75]”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [75] Chang, 2018, SOST/Sclerostin improves posttraumatic osteoarthritis and inhibits MMP2/3 expression after injury, J. Bone Miner. Res. source
The Results report that TNFα-dependent Sost activation occurs in injured mouse joints, and the Discussion says elevated sclerostin reduces the expression and activity of cartilage-degrading MMP2/3 after injury. The Discussion proposes a role for IL1 generally but specifically mentions evidence for IL1α, not IL-1β; the claim’s identification of IL-1β as a trigger is therefore unsupported by our copy (page numbers unavailable). (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
A number of physiopathological conditions are characterized by excessive osteoclast activity, including menopause, juvenile Paget's disease of bone, inflammatory joint diseases, bone cancers such as multiple myeloma, and glucocorticoid therapy.
“a number of physiopathological conditions are characterized by excessive osteoclast activity. These include but are not limited to menopause, juvenile Paget’s disease of bone, inflammatory joint diseases, bone cancers such as multiple myeloma, and glucocorticoid therapy [1,2]”
Quote in the paperNot a substantial claim1 of 2 sources checked - Premisecitation
IGF-1 has been shown to increase rodent humerus periosteal bone formation by 37% during a 10 day Space Shuttle flight.
“Insulin-like growth factor (IGF)-1, which plays a major role in all phases of bone and cartilage growth, has been shown to increase rodent humerus periosteal bone formation by 37% during a 10 day Space Shuttle flight [8]”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [8] Smith, J.K. (2020). Microgravity, bone homeostasis, and insulin-like growth factor-1. Appl. Sci., 10. source
- Premisecitation
Osteoprotegerin-Fc given subcutaneously to mice flown for 12 days in space produced a sustained suppression of bone resorption.
“Osteoprotegerin-Fc given subcutaneously to mice flown for 12 days in space produced a sustained suppression of bone resorption”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [77] Lloyd, 2015, Osteoprotegerin is an effective countermeasure for spaceflight-induced bone loss in mice, Bone source
- Interpretationreasoning
The bone loss experienced by astronauts in space is the result of microgravity-related impairment of osteocyte and osteoblast function and the consequent upregulation of osteoclast-mediated bone resorption.
“This loss is the result of microgravity-related impairment of osteocyte and osteoblast function and the consequent upregulation of osteoclast-mediated bone resorption.”
Quote in the paperSubstantial claim- Rests on an assumption: Astronauts lose 1.0% to 1.5% of their bone mass for every month they spend in space despite adherence to diets and exercise regimens designed to protect their musculoskeletal systems.
- Premisecitation
Differentiation of HSCs into osteoclast precursors requires expression of PU.1, MITF, and TfE3, which initiate expression of C-Fms.
“The differentiation of HSCs into osteoclast precursors requires the expression of spleen focus-forming virus proviral integrin 1 (PU.1), heterodimeric complex of microphthalmia-associated transcription factor (MITF), and transcription factor E3 (TfE3), which initiate the expression of the colony stimulating factor-1 receptor (C-Fms) [18].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Boyce, 2013, Advances in the regulation of osteoclasts and osteoclast functions, J. Dent. Res. source
- Premisecitation
In unstimulated HSCs, TRAFs 2 and 3 and cIAP1 form a complex that polyubiquitinates NIK, leading to its proteasomal degradation and very low levels of NF-κB.
“In unstimulated HSCs, TRAFs 2 and 3, and c baculoviral inhibitor of apoptosis repeat-containing protein 2 (cIAP1) form a complex that polyubiquitinates NF-κB-inducing kinase (NIK), which is transported to the proteasome for degradation, resulting in very low levels of NF-κB in unstimulated HSCs [18].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Boyce, 2013, Advances in the regulation of osteoclasts and osteoclast functions, J. Dent. Res. source
- Premisecitation
IL-12 added to TNF-α-stimulated cultures induces osteoclast apoptosis by upregulating expression of Fas/Fas ligands.
“Using mouse bone marrow cultures, Kitaura and associates found that IL-12 when added to TNF-α-stimulated cultures induced osteoclast apoptosis by upregulating their expression of Fas/Fas ligands [45].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Kitaura, 2002, Effect of IL-12 on TNF-α -mediated osteoclast formation in bone marrow cells: Apoptosis mediated by Fas/Fas ligand interaction, J. Immunol. source
- Premisecitation
In the same rat spaceflight study, femoral trabecular bone at the site of muscular insertions and vertebral bone showed no significant changes compared to ground controls.
“In contrast, femoral trabecular bone at the site of muscular insertions and vertebral bone showed no significant changes when compared to ground controls.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [57] Vico, 1988, Trabecular bone remodeling after seven days of weightlessness exposure (BIOCOSMOS 1667), Am. J. Physiol. source
- Premisecitation
Low doses of IL-4 inhibit RANKL-induced osteoclastogenesis in monocytes/macrophages and bone marrow osteoclast precursors by downregulating NFATc1 mRNA expression.
“Mohamed and associates found that low doses of IL-4 inhibited RANKL-induced osteoclastogenesis in monocytes/macrophages and in bone marrow osteoclast precursors by downregulating NFATc1 mRNA expression [39].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Mohamed, 2005, Interleukin-4 inhibits RANKL-induced expression of NFATc1 and c-Fos: A possible mechanism for downregulation of osteoclastogenesis, Biochem. Biophys. Res. Commun. source
- Premisecitation
IL-1β enhances the ability of TNF-α to upregulate bone resorption by TRAP-positive multinucleated cells.
“Azuma and associates found that IL-1β enhanced the ability of TNF-α to upregulate bone resorption by TRAP-positive multinucleated cells [31].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Azuma, 2000, Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts, J. Biol. Chem. source
- Premisecitation
Five days of spaceflight aboard the COSMOS 1514 biologic satellite increased the number of TRAP-positive osteoclasts per mm2 of thoracic and lumbar vertebrae.
“Using similar methods, the same investigators had previously shown that 5 days of spaceflight aboard the COSMOS 1514 biologic satellite increased the number of TRAP-positive osteoclasts per mm2 of thoracic and lumbar vertebrae [58]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [58] Vico, 1987, Effects of weightlessness on bone mass and osteoclast number in pregnant rats after a five-day spaceflight (COSMOS 1514), Bone source
- Premisecitation
Microgravity increased the resorptive activity of osteoclasts compared to ground controls, based on analysis of approximately 16,000 resorptive pits on Osteologic slides.
“In contrast, on analyzing approximately 16,000 resorptive pits on Osteologic slides, they found that microgravity increased the resorptive activity of osteoclasts when compared to that of ground controls, underscoring the resilience of these cells to the effects of zero gravity [54].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [54] Nabavi, 2011, Effects of microgravity on osteoclast bone resorption and osteoblast cytoskeletal organization and adhesion, Bone source
- Premisecitation
IL-10 inhibits osteoclastogenesis by downregulating RANKL-induced expression of c-Fos and its downstream target NFATc1.
“Using a RAW267.4 macrophage cell line and murine bone marrow cells, Mohamed and associates reported that IL-10 inhibited osteoclastogenesis by downregulating RANKL-induced expression of c-Fos and its downstream target, NFATc1 [43].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Mohamed, 2007, Interleukin-10 inhibits RANKL-mediated expression of NFATc1 in part via suppression of c-Fos and c-Jun in RAW264.7 cells and mouse bone marrow cells, Bone source
- Premisecitation
Fourteen days of flight aboard the COSMOS 2044 space shuttle increased osteoclast number and resorptive activity in the male Wistar rat tibial metaphysis.
“and that 14 days of flight aboard the COSMOS 2044 space shuttle increased the osteoclast number and resorptive activity in the male Wistar rat tibial metaphysis [59].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [59] Vico, 1985, Histomorphometric analysis of cancellous bone from COSMOS 2044 rats, J. Appl. Physiol. source
- Premisecitation
IL-1α stimulates osteoclastogenesis by upregulating M-CSF and PGE2 production and by decreasing OPG production in osteoblasts.
“Tanabe and associates examined the effect of IL-1α on cultures of rat osteoblasts and hematopoietic stem cells and found that it stimulated osteoclastogenesis by upregulating M-CSF and prostaglandin E2 (PGE2) production and by decreasing OPG production in osteoblasts [33].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Tanabe, 2005, IL-alpha stimulates the formation of osteoclast-like cells by increasing M-CSF and PGE2 production and decreasing OPG production by osteoblasts, Life Sci. source
- Premisecitation
Bone morphogenetic protein-1 in conjunction with RANKL increases the differentiation and survival of osteoclasts.
“Bone morphogenetic protein-1 in conjunction with RANKL has been shown to increase the differentiation and survival of osteoclasts [36].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Itoh, 2001, Bone morphogenic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kappaB ligand, Endocrinology source
- Interpretationreasoning
Along with the diminished force of muscular contraction on bone, microgravity-related changes in osteoblasts, osteocytes, and osteoclasts account for the space-related loss of bone mass.
“Along with the diminished force of muscular contraction on bone, these changes account for the space-related loss of bone mass.”
Quote in the paperSubstantial claim - Premisecitation
TGF-β, released from the bone matrix during bone resorption, enhances osteoclast differentiation in RANKL- and M-CSF-stimulated HSC cultures.
“Transforming growth factor-β, which is released from the bone matrix during bone resorption, has been shown to enhance osteoclast differentiation in RANKL- and M-CSF-stimulated HSC cultures [35].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Quinn, 2001, Transforming growth factor beta affects osteoclast differentiation via direct and indirect actions, J. Bone Miner. Res. source
- Interpretationcitation
Both live animal and cell culture studies are uniform in documenting an upregulation of osteoclast numbers, resorptive activity, and resorption-related gene expression in the microgravity of space.
“Both live animal and cell culture studies are uniform in documenting an upregulation of osteoclast numbers, resorptive activity, and resorption-related gene expression in the microgravity of space (bone volumes, masses) (Figure 7).”
Quote in the paperSubstantial claim - Premisecitation
Increased syncytin-A production in simulated microgravity upregulated osteoclastogenesis.
“increased syncytin-A production in simulated microgravity upregulated osteoclastogenesis”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [69] Ethiraj, 2018, Microgravity modulation of syncytin-A expression enhance osteoclast formation, J. Cell. Biochem. source
- Rests on an assumption: Simulated microgravity using the RWV is a valid model for actual microgravity conditions in space.
- Premisecitation
Simulated microgravity increased osteoclastogenesis by twofold in RAW 264.7 osteoclast progenitor cells compared to ground controls.
“Sambandam and associates found that simulated microgravity increased osteoclastogenesis by twofold”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [66] Sambandam, 2010, Microarray profile of gene expression during osteoclast differentiation in modelled microgravity, J. Cell. Biochem. source
- Rests on an assumption: Simulated microgravity using the RWV is a valid model for actual microgravity conditions in space.
- Interpretationreasoning
The reasons include microgravity-induced disruption of osteoblast nuclei, cytoskeleton, and intracellular adhesins.
“microgravity-induced disruption of osteoblast nuclei, cytoskeleton, and intracellular adhesins”
Quote in the paperSubstantial claim - Premisecitation
Simulated microgravity upregulated production/expression of factors involved in osteoclastogenesis, including cytokines, growth factors, proteases, signaling proteins, and transcription factors c-Jun, MITF, and CREB, compared to ground controls.
“upregulated the production/expression of factors involved in osteoclastogenesis, including cytokines, growth factors, proteases, signaling proteins, and transcription factors c-Jun, MITF, and CREB as compared to ground controls [66]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [66] Sambandam, 2010, Microarray profile of gene expression during osteoclast differentiation in modelled microgravity, J. Cell. Biochem. source
- Rests on an assumption: Simulated microgravity using the RWV is a valid model for actual microgravity conditions in space.
- Interpretationreasoning
The reasons include increased secretion of sclerostin by pre-apoptotic osteocytes.
“the increased secretion of sclerostin by pre-apoptotic osteocytes”
Quote in the paperSubstantial claim - Premisecitation
Inhibition of syncytin-A decreased microgravity-induced osteoclastogenesis.
“inhibition of syncytin-A decreased microgravity-induced osteoclastogenesis”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [69] Ethiraj, 2018, Microgravity modulation of syncytin-A expression enhance osteoclast formation, J. Cell. Biochem. source
- Rests on an assumption: Simulated microgravity using the RWV is a valid model for actual microgravity conditions in space.
- Interpretationreasoning
The reasons for bone unloading effects include reduction of bone-loading signals normally transduced by shear stresses and hydraulic pressures exerted on osteocytes.
“the reduction of bone-loading signals normally transduced by shear stresses and hydraulic pressures exerted on osteocytes”
Quote in the paperSubstantial claim - Interpretationreasoning
Bone loss is the consequence of microgravity-related impairment of osteocyte and osteoblast function and the consequent upregulation of osteoclast-mediated bone resorption.
“Bone loss is the consequence of microgravity-related impairment of osteocyte and osteoblast function and the consequent upregulation of osteoclast-mediated bone resorption.”
Quote in the paperNot a substantial claim- Rests on an assumption: Simulated microgravity using the RWV is a valid model for actual microgravity conditions in space.
- Classified as probably not a substantial claim. 9
- May combine two claims. 32
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOsteoclasts adhere to bone by means of the sealing zone, a belt of densely packed microtubule-stabilized podosomes, and podosomes mediate adhesion via integrin αvβ3, the major osteoclast integrin.
“Osteoclasts adhere to bone by means of the sealing zone, a belt of densely packed microtubule-stabilized podosomes (Figure 6). Podosomes mediate adhesion via integrin αvβ3, the major osteoclast integrin.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [2] Blangy, 2020, The osteoclast—Current understanding and therapeutic perspectives for osteoporosis, J. Cell Sci. source
May combine two claims.
PremisecitationHSCs may be recycled to the bone marrow by binding S1P to S1PR1 or stay at bone surfaces where they evolve into mature osteoclasts by binding M-CSF and RANKL produced primarily by osteoblasts, osteocytes, and stromal cells.
“HSCs may then be recycled to the bone marrow by binding S1P to type-1 receptors (S1PR1) or stay at bone surfaces where they evolve into mature osteoclasts by binding M-CSF and RANKL produced primarily by osteoblasts, osteocytes, and stromal cells [15,16] (Figure 2).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [15] Ishii, 2009, Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis, Nature source
The paper’s discussion of precursor recirculation (indexed as Abstract; page unavailable) supports S1P–S1P1 signaling and RANKL-associated maturation at the bone surface. But it describes monocyte-lineage osteoclast precursors moving from bone tissue into the blood, not HSCs returning to bone marrow. The Cell culture methods identify M-CSF-dependent precursors, but the paper does not establish that M-CSF and RANKL are produced primarily by the three cell types named in the claim. (LLM, conf=0.89)
Experimental — accuracy not yet measured - cites [16] Ishii, 2011, The role of sphingosine 1-phosphjate in migration of osteoclast precursors; an application of intravital two-photon microscopy, Mol. Cells source
The ‘Application of intravital imaging to the analysis of cell behavior in bone’ section says S1PR1-mediated chemotaxis returns osteoclast precursors from bone tissue to blood vessels, not to bone marrow. It also reports that precursors remaining on bone surfaces can develop into mature osteoclasts. The paper discusses osteoclast precursors rather than HSCs and does not support the specified M-CSF/RANKL mechanism or the listed cellular sources. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe osteoclast cytoskeleton is made of four categories of filamentous structures and fulfills essential functions including cell adhesion, migration, contractility, division, vesicular transport, and bone resorption.
“The osteoclast cytoskeleton is made of filamentous structures that belong to one of four categories: polarized actin filaments; polarized microtubules; non-polarized intermediate filaments; or non-polarized septin filaments. The cytoskeleton fulfills essential functions including cell adhesion, migration, contractility, division, vesicular transport, and bone resorption [2,3,4,5,6].”
Quote in the paperNot a substantial claim5 of 5 sources checked- cites [2] Blangy, 2020, The osteoclast—Current understanding and therapeutic perspectives for osteoporosis, J. Cell Sci. source
- cites [3] Svitkina, 2018, The actin cytoskeleton and actin-based motility, Cold Spring Harb. Perspect. Biol. source
The Introduction (page unavailable) describes actin filaments as polar, and the Abstract and section 5.2 (page unavailable) describe roles in adhesion, migration, contraction, intracellular organelle movement, and cell division. The paper does not establish the four-category classification for osteoclasts or address bone resorption. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [4] LaFlamme, 2018, Integrin and microtubule crosstalk in the regulation of cellular processes, Cell Mol. Life Sci. source
The Introduction describes microtubules as polarized filaments involved in vesicular trafficking, migration, and mitosis. The section on adhesion-site turnover also links microtubules to cell adhesion and migration. Our copy does not establish the four-category classification for osteoclasts or the claimed roles in osteoclast contractility and bone resorption; page numbers were not provided. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [5] Martínez, P.T., Navajas, P.L., and Lietha, D. (2020). FAK Structure and regulation by membrane interactions and force in focal adhesions. Biomolecules, 10. source
The Introduction describes an actin-cytoskeleton connection that provides traction during cell migration as actomyosin fibres contract, supporting part of the functional claim. It does not address osteoclasts, the four filament categories, or the claimed roles in division, vesicular transport, and bone resorption. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [6] Burke, 2019, Chain reaction: LINC complexes and nuclear positioning, F1000Research source
The LINC diversity section discusses actin, microtubules, and intermediate filaments as cytoskeletal systems. It does not identify four categories, mention septin filaments, or establish the listed functions for osteoclasts, including bone resorption. Page numbers are not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn the center of the sealing zone, the osteoclast membrane differentiates into a ruffled border, where it secretes hydrochloric acid and proteases to dissolve hydroxyapatite crystals and bone matrix.
“In the center of the sealing zone, the osteoclast membrane differentiates into a ruffled border, where it secretes hydrochloric acid and proteases (cathepsin-K, MMP9, and MMP14) to dissolve hydroxyapatite crystals and bone matrix, respectively [2].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [2] Blangy, 2020, The osteoclast—Current understanding and therapeutic perspectives for osteoporosis, J. Cell Sci. source
May combine two claims.
PremisecitationTNF-α induces osteoclastogenesis in RANKL- and M-CSF-positive hematopoietic cell precursors, with effects mediated by TNF-α receptors type 1 and type 2, the former being most effective in inducing differentiation of TRAP-positive multinucleated cells.
“TNF-α induces osteoclastogenesis in RANKL- and M-CSF-positive hematopoietic cell precursors [29,30], where its effects are mediated by TNF-α receptors type 1 (p55r) and type 2 (p75r), the former being the most effective in inducing the differentiation of TRAP-positive multinucleated cells [31].”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [29] Lam, 2000, TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand, J. Clin. Investig. source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [30] Kitaura, 2004, Marrow stromal cells and osteoclast precursors differentially contribute to TNF-alpha-induced osteoclastogenesis in vivo, J. Immunol. source
- cites [31] Azuma, 2000, Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts, J. Biol. Chem. source
May combine two claims.
PremisecitationIn RANKL-activated HSCs, polyubiquitination of NIK is inhibited and TRAF6 activates a cascade of kinases including ERK, p38, JNK, PI3K, Akt, and IkB kinases.
“In RANKL-activated HSCs, polyubiquitination of NIK is inhibited [18], and TRAF6 activates a cascade of kinases, including extracellular regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), c-jun N-terminal kinase (JNK), phosphatidylinositol-3 kinase (PI3K), and Akt and IkB kinases [20,21].”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [18] Boyce, 2013, Advances in the regulation of osteoclasts and osteoclast functions, J. Dent. Res. source
- cites [20] Kim, 2014, Regulation of NFATc1 in osteoclast differentiation, J. Bone Metab. source
The Introduction says RANKL recruits TRAF6 and links it to downstream ERK, p38, and JNK signaling in osteoclast precursor cells. The transcriptional-regulation section describes IκB kinases in RANKL signaling, but does not link them specifically to TRAF6; the cited passages do not establish PI3K or Akt activation or identify the cells as HSCs. The NIK-polyubiquitination clause carries a separate citation [18], so it is not assessed against this source. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [21] Zawawi, 2012, Regulation of ITAM adapter molecules and their receptors by inhibition of calcineurin-NFAT signaling during late stage osteoclast differentiation, Biochem. Biophys. Res. Commun. source
May combine two claims.
PremisecitationOsteocytes respond to hydrostatic and fluid shear stresses in the lacunae and canaliculi and are largely responsible for the control of bone homeostasis.
“Osteocytes respond to hydrostatic and fluid shear stresses in the lacunae and canaliculi and are largely responsible for the control of bone homeostasis [8] (Figure 1).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [8] Smith, J.K. (2020). Microgravity, bone homeostasis, and insulin-like growth factor-1. Appl. Sci., 10. source
May combine two claims.
PremisecitationThe RANKL-activated kinase cascade requires Lys63-linked TRAF-6 auto-ubiquitination and initiates transcription of AP-1, c-Fos, NF-κB, and NFATc1, the master regulator of osteoclast differentiation.
“This cascade requires Lys63-linked TRAF-6 auto-ubiquitination [22] and initiates the transcription of activator protein-1 (AP-1), c-Fos, NF-κB, and nuclear factor of activated T cells cytoplasmic calcineurin-dependent 1 (NFATc1), the master regulator of osteoclast differentiation [20,23,24].”
Quote in the paperNot a substantial claim2 of 4 sources checked- cites [22] Lamothe, 2007, TRAF-s ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation, Biochem. Biophys. Res. Commun. source
- cites [20] Kim, 2014, Regulation of NFATc1 in osteoclast differentiation, J. Bone Metab. source
The Introduction says RANKL recruits TRAF6 and activates downstream pathways and transcription factors including NF-κB, c-Fos, and NFATc1. The section on transcriptional regulation identifies c-Fos as an AP-1 member, describes RANKL-induced NFATc1 expression, and calls NFATc1 a master factor. It does not say that the cascade initiates transcription of AP-1 and NF-κB; it describes their activation instead. The Lys63-linked TRAF6 auto-ubiquitination clause has its own citation [22] and is not assessed against this source. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [23] Kobayashi, 2009, Action of RANKL and OPG for osteoclastogenesis, Crit. Rev. Eukaryot. Gene Expr. source
- cites [24] Takayanagi, 2009, Ca2+ NFATc1 signaling is an essential axis of osteoclast differentiation, Immunol. Rev. source
May combine two claims.
PremisecitationIn medaka fish during spaceflight, in vivo signals of osteoclast activity were upregulated at days 4 and 6 after launch, and expression of osteoclast-specific genes TRAP, cathepsin K, and MMP9 were upregulated on day two of the flight.
“They found that in vivo signals of osteoclast activity were upregulated at days 4 and 6 after launch, and that expression of osteoclast-specific genes TRAP, cathepsin K, and MMP9 were upregulated on day two of the flight [61].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [61] Chatani, 2016, Acute transcriptional up-regulation specific to osteoblasts/osteoclasts in medaka fish immediately after exposure to microgravity, Sci. Rep. source
May combine two claims.
PremisecitationIn eight C57BL/6 mice flown for 15 days on STS-131, microgravity reduced bone volume by 6.3% and bone thickness by 11.9% and increased bone-surface TRAP-positive osteoclasts by 170% compared to ground controls, indicating enhanced osteoclast-mediated bone resorption.
“They found that microgravity reduced the bone volume by 6.3% and bone thickness by 11.9% and increased the number of bone-surface TRAP-positive osteoclasts by 170% compared to that of ground controls, indicating enhanced osteoclast-mediated bone resorption.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [60] Blaber, E.A., Dvorochkin, N., Lee, C., Alwood, J.S., Yousuf, R., Pianetta, P., Globus, R.K., Burns, B.P., and Almeida, E.A. (2013). Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21. PLoS ONE, 8. source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIL-1β has also been reported to suppress osteoclast formation by upregulating OPG production by chondrocytes.
“However, IL-1β has also been reported to suppress osteoclast formation by upregulating OPG production by chondrocytes [34].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [34] Watanabe, 2009, IL-1 beta suppresses the formation of osteoclasts by increasing OPG production via an autocrine mechanism involving celecoxib-related prostaglandins in chondrocytes, Mediat. Inflamm. source
May combine two claims.
PremisecitationOsteocytes control osteoclast activity by secreting sclerostin, which increases bone resorption by downregulating osteoblast OPG production and decreases osteoblastogenesis by inhibiting Wnt/β-catenin signaling pathways in osteoblast precursors.
“Osteocytes control osteoclast activity by secreting sclerostin, which increases bone resorption by downregulating osteoblast OPG production and decreases osteoblastogenesis by inhibiting Wnt/β-catenin signaling pathways in osteoblast precursors [53].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [53] De Maré, A.S., D’Haese, P.C., and Verhulst, A. (2020). The role of sclerostin in bone and ectopic calcification. Int. J. Mol. Sci., 21. source
May combine two claims.
InterpretationcitationOsteoclasts maintain their ability to resorb bone in microgravity, in contrast to osteoblasts and osteocytes, which are adversely affected by microgravity.
“In stark contrast to the devastating effects of microgravity on osteoblasts, whose cytoskeletons may implode do to the failure of microtubules and actin filaments [54,55], and osteocytes, which undergo apoptosis as early as three days into space flight [56], osteoclasts maintain their ability to resorb bone in microgravity.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [54] Nabavi, 2011, Effects of microgravity on osteoclast bone resorption and osteoblast cytoskeletal organization and adhesion, Bone source
- cites [55] 2003, Function of the cytoskeleton in gravisensing during spaceflight, Adv. Space Res.
Not checked in the free run.
- cites [56] Gerbaix, 2017, One-month spaceflight compromises the bone microstructure, tissue-level mechanical properties, osteocyte survival and lacunar volume in mature mice skeletons, Sci. Rep. source
The citation [56] is attached to the claim that osteocytes undergo apoptosis as early as three days into spaceflight. The Discussion reports increased empty osteocyte lacunae after a 30-day flight, suggesting osteocyte death, but does not establish apoptosis at three days. It also reports increased bone resorption, though that is not the part of the sentence specifically attached to [56]. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationConditions of microgravity and simulated microgravity decrease the mineral content and cortical and trabecular microstructures of bone.
“conditions of microgravity and simulated microgravity decrease the mineral content and cortical and trabecular microstructures of bone”
Quote in the paperSubstantial claim4 of 10 sources checked- cites [57] Vico, 1988, Trabecular bone remodeling after seven days of weightlessness exposure (BIOCOSMOS 1667), Am. J. Physiol. source
- cites [58] Vico, 1987, Effects of weightlessness on bone mass and osteoclast number in pregnant rats after a five-day spaceflight (COSMOS 1514), Bone source
- cites [59] Vico, 1985, Histomorphometric analysis of cancellous bone from COSMOS 2044 rats, J. Appl. Physiol. source
- cites [60] Blaber, E.A., Dvorochkin, N., Lee, C., Alwood, J.S., Yousuf, R., Pianetta, P., Globus, R.K., Burns, B.P., and Almeida, E.A. (2013). Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21. PLoS ONE, 8. source
The Results (page unavailable) report reduced pelvic bone volume fraction and thickness after spaceflight, supporting a microgravity-related structural change. They report no difference in bone mineral density, however, and the paper does not show that simulated microgravity decreases cortical and trabecular microstructure. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [61] Chatani, 2016, Acute transcriptional up-regulation specific to osteoblasts/osteoclasts in medaka fish immediately after exposure to microgravity, Sci. Rep. source
The Discussion (page unavailable) says bone mineral density decreases under microgravity, and the Abstract reports bone and calcium loss during spaceflight. The copy does not say that simulated microgravity decreases bone mineral content or that either condition degrades cortical and trabecular microstructures. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [62] Tamma, 2009, Microgravity during spaceflight directly affects in vitro osteoclastogenesis and bone resorption, FASEB J. source
- cites [63] Saxena, 2011, Modeled microgravity and hindlimb unloading sensitize osteoclast precursors to RANKL-mediated osteoclastogenesis, J. Bone Miner. Metab. source
- cites [64] Aguirre, 2006, Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss, J. Bone Miner. Res. source
- cites [65] Rucci, 2007, Modeled microgravity stimulates osteoclastogenesis and bone resorption by increasing osteoblast RANKL/OPG ratio, J. Cell. Biochem. source
The Discussion reports reduced trabecular bone volume, thickness, and number in rats after space flight. The paper also reports increased bone resorption in a simulated-microgravity cell-culture experiment, but it does not establish decreased bone mineral content or cortical microstructure under either condition, or decreased trabecular microstructure under simulated microgravity. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [66] Sambandam, 2010, Microarray profile of gene expression during osteoclast differentiation in modelled microgravity, J. Cell. Biochem. source
May combine two claims.
PremisecitationConditions of microgravity and simulated microgravity increase osteoclast differentiation, fusion, and expression of regulatory and osteoclast-specific genes.
“increase osteoclast differentiation, fusion, and expression of regulatory and osteoclast-specific genes”
Quote in the paperSubstantial claim4 of 10 sources checked- cites [57] Vico, 1988, Trabecular bone remodeling after seven days of weightlessness exposure (BIOCOSMOS 1667), Am. J. Physiol. source
- cites [58] Vico, 1987, Effects of weightlessness on bone mass and osteoclast number in pregnant rats after a five-day spaceflight (COSMOS 1514), Bone source
- cites [59] Vico, 1985, Histomorphometric analysis of cancellous bone from COSMOS 2044 rats, J. Appl. Physiol. source
- cites [60] Blaber, E.A., Dvorochkin, N., Lee, C., Alwood, J.S., Yousuf, R., Pianetta, P., Globus, R.K., Burns, B.P., and Almeida, E.A. (2013). Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21. PLoS ONE, 8. source
The Results section ('Spaceflight Causes Osteoclast and Osteocyte-Mediated Bone Loss') reports more osteoclasts and greater osteoclast-covered bone surface after spaceflight, supporting increased osteoclastic activity in microgravity. It does not establish increased osteoclast differentiation or fusion, or increased expression of regulatory and osteoclast-specific genes in osteoclasts; the reported gene-expression changes concern bone tissue and osteocytes. The study also did not test simulated microgravity. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [61] Chatani, 2016, Acute transcriptional up-regulation specific to osteoblasts/osteoclasts in medaka fish immediately after exposure to microgravity, Sci. Rep. source
The Discussion and Results (page numbers unavailable) report increased osteoclast-related gene expression in medaka exposed to actual microgravity, along with up-regulation of transcription-regulatory genes. The paper does not show increased osteoclast differentiation or fusion after exposure, and its experiment did not test simulated microgravity. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [62] Tamma, 2009, Microgravity during spaceflight directly affects in vitro osteoclastogenesis and bone resorption, FASEB J. source
- cites [63] Saxena, 2011, Modeled microgravity and hindlimb unloading sensitize osteoclast precursors to RANKL-mediated osteoclastogenesis, J. Bone Miner. Metab. source
The Abstract and Discussion (pages unavailable) report that modeled microgravity sensitized osteoclast precursors: after RANKL stimulation, they formed large multinucleated osteoclasts and showed increased TRAP and cathepsin K expression. The paper also reports activation of osteoclastogenesis-related signaling molecules, but says modeled microgravity alone did not increase osteoclastogenesis. It mentions increased differentiation during actual spaceflight as a finding from another study, rather than demonstrating the full differentiation, fusion, and gene-expression claim under actual microgravity. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [64] Aguirre, 2006, Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss, J. Bone Miner. Res. source
- cites [65] Rucci, 2007, Modeled microgravity stimulates osteoclastogenesis and bone resorption by increasing osteoblast RANKL/OPG ratio, J. Cell. Biochem. source
The 'Effect of Microgravity on Osteoclastogenesis and Bone Resorption' section reports increased osteoclastogenesis in mouse bone-marrow cultures exposed to conditioned medium from osteoblasts grown under modeled microgravity. The Discussion reports an increased osteoblast RANKL/OPG ratio, but our copy does not establish increased osteoclast fusion or expression of osteoclast-specific genes, nor does this experiment test actual microgravity. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [66] Sambandam, 2010, Microarray profile of gene expression during osteoclast differentiation in modelled microgravity, J. Cell. Biochem. source
May combine two claims.
PremisecitationIn mice subjected to 4 weeks of 30° head-down hindlimb unloading, hindlimb unloading caused a decrease in femoral bone mineral density and cortical and trabecular bone microstructure, associated with upregulation of osteoclastogenesis-related signaling molecules ERK, p38, PLCγ2, and NFATc1 and osteoclast-specific markers TRAP and cathepsin K.
“They found that hindlimb unloading caused a decrease in femoral bone mineral density and cortical and trabecular bone microstructure. This loss was associated with an upregulation in osteoclastogenesis-related signaling molecules ERK, p38, PLCγ2, and NFATc1 and osteoclast-specific markers TRAP and cathepsin K.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [63] Saxena, 2011, Modeled microgravity and hindlimb unloading sensitize osteoclast precursors to RANKL-mediated osteoclastogenesis, J. Bone Miner. Metab. source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationSimulated microgravity enhanced osteoclastogenesis by decreasing osteoblast production of OPG, increasing RANKL/OPG ratios.
“The investigators found that simulated microgravity enhanced osteoclastogenesis by decreasing osteoblast production of OPG (increasing RANKL/OPG ratios) [65].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [65] Rucci, 2007, Modeled microgravity stimulates osteoclastogenesis and bone resorption by increasing osteoblast RANKL/OPG ratio, J. Cell. Biochem. source
May combine two claims.
PremisecitationConditions of microgravity and simulated microgravity decrease osteoblastogenesis and osteoblast secretion of OPG.
“decrease osteoblastogenesis and osteoblast secretion of OPG”
Quote in the paperSubstantial claim4 of 10 sources checked- cites [57] Vico, 1988, Trabecular bone remodeling after seven days of weightlessness exposure (BIOCOSMOS 1667), Am. J. Physiol. source
- cites [58] Vico, 1987, Effects of weightlessness on bone mass and osteoclast number in pregnant rats after a five-day spaceflight (COSMOS 1514), Bone source
- cites [59] Vico, 1985, Histomorphometric analysis of cancellous bone from COSMOS 2044 rats, J. Appl. Physiol. source
- cites [60] Blaber, E.A., Dvorochkin, N., Lee, C., Alwood, J.S., Yousuf, R., Pianetta, P., Globus, R.K., Burns, B.P., and Almeida, E.A. (2013). Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21. PLoS ONE, 8. source
The Discussion (page unavailable) links spaceflight microgravity to reduced osteogenesis and reports increased p21 staining in osteoblast nuclei, although it presents p21-mediated inhibition as a possibility. The Introduction also discusses simulated-microgravity studies. Neither the supplied passages nor searches for OPG and osteoprotegerin show that this paper reports decreased osteoblast secretion of OPG. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [61] Chatani, 2016, Acute transcriptional up-regulation specific to osteoblasts/osteoclasts in medaka fish immediately after exposure to microgravity, Sci. Rep. source
The Results section, “Enhancement of osteoblast signals under microgravity” (page unavailable), reports increased osteoblast-marker fluorescence in medaka, but does not measure osteoblastogenesis. The Discussion (page unavailable) describes altered osteoblast gene expression; neither passage addresses OPG secretion or establishes what simulated microgravity does to either outcome. Searches for OPG/osteoprotegerin and decreased osteoblastogenesis found no decisive passage. (LLM, conf=0.72)
Experimental — accuracy not yet measured - cites [62] Tamma, 2009, Microgravity during spaceflight directly affects in vitro osteoclastogenesis and bone resorption, FASEB J. source
- cites [63] Saxena, 2011, Modeled microgravity and hindlimb unloading sensitize osteoclast precursors to RANKL-mediated osteoclastogenesis, J. Bone Miner. Metab. source
The Discussion (page unavailable) says that osteoblastogenesis is inhibited in modeled microgravity, citing the authors’ earlier work. Our copy does not report decreased osteoblast secretion of OPG; its Discussion mentions osteoprotegerin only as part of a treatment for unloading-induced bone loss. The study also found no significant reduction in bone-formation parameters in its hindlimb-unloaded mice. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [64] Aguirre, 2006, Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss, J. Bone Miner. Res. source
- cites [65] Rucci, 2007, Modeled microgravity stimulates osteoclastogenesis and bone resorption by increasing osteoblast RANKL/OPG ratio, J. Cell. Biochem. source
The Discussion reports that osteoblasts released less OPG under modeled microgravity. It also describes reduced osteoblast differentiation in earlier, longer-duration studies, but this paper found no effect on differentiation after its 24-hour exposure. The unqualified claim that microgravity decreases osteoblastogenesis therefore goes beyond this paper’s own findings. (LLM, conf=0.89)
Experimental — accuracy not yet measured - cites [66] Sambandam, 2010, Microarray profile of gene expression during osteoclast differentiation in modelled microgravity, J. Cell. Biochem. source
May combine two claims.
PremisecitationModeled microgravity increases osteoclast precursor differentiation with consequent increases in bone resorption.
“They concluded that modeled microgravity increases osteoclast precursor differentiation with consequent increases in bone resorption [63].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [63] Saxena, 2011, Modeled microgravity and hindlimb unloading sensitize osteoclast precursors to RANKL-mediated osteoclastogenesis, J. Bone Miner. Metab. source
The Discussion reports that modeled microgravity sensitized osteoclast precursors to differentiation after subsequent RANKL treatment; it did not enhance osteoclastogenesis without RANKL. The Results on hindlimb unloading report more osteoclasts and bone loss, but the paper does not establish that modeled-microgravity-induced differentiation consequently increased bone resorption. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMany studies on bone homeostasis have been motivated by the need to find treatments capable of modifying osteoclast activity without inducing osteopetrosis.
“many of the studies on bone homeostasis have been motivated by the need to find treatments capable of modifying osteoclast activity without inducing osteopetrosis [8]”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [8] Smith, J.K. (2020). Microgravity, bone homeostasis, and insulin-like growth factor-1. Appl. Sci., 10. source
The Discussion says many bone-homeostasis studies in space and microgravity models are motivated by finding treatments to prevent bone loss. The Osteoclasts and Sclerostin sections discuss osteoclast activity and a treatment that decreases bone resorption, but our copy does not say that avoiding osteopetrosis motivates those studies. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationOdanacatib prevents pathological bone loss while preserving bone formation but failed in clinical phase III trials due to increased risk of stroke.
“odanacatib, was shown to prevent pathological bone loss while preserving bone formation but failed in clinical phase III trials due to increased risk of stroke [72]”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [72] Stone, 2019, Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis, Br. J. Clin. Pharmacol. source
May combine two claims.
PremisecitationMelatonin stimulated calcitonin mRNA expression and decreased RANKL mRNA expression in cultured fish scales during an 11-day space flight.
“melatonin, a well-tolerated and widely available compound, stimulated calcitonin mRNA expression and decreased RANKL mRNA expression in cultured fish scales (a surrogate for bone cultures) during an 11-day space flight”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [78] Ikegame, 2019, Melatonin is a potential drug for the prevention of bone loss during spaceflight, J. Pineal Res. source
The Results section on bone-related gene expression reports that melatonin increased Calcitonin mRNA and suppressed the microgravity-associated increase in Rankl mRNA in regenerating goldfish scales. The Methods section on the space-flight experiment says the scales were incubated in flight for 86 hours, not 11 days; our copy does not substantiate the claimed duration for these measurements. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe calcineurin pathway is a key costimulatory pathway of NFATc1 and an important signaling component of a number of immune cell receptors.
“This activates cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and the calcineurin pathway [21,24,25,27], a key costimulatory pathway of NFATc1 [21,23] and an important signaling component of a number of immune cell receptors [28] (Figure 4 and Figure 5).”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [21] Zawawi, 2012, Regulation of ITAM adapter molecules and their receptors by inhibition of calcineurin-NFAT signaling during late stage osteoclast differentiation, Biochem. Biophys. Res. Commun. source
- cites [24] Takayanagi, 2009, Ca2+ NFATc1 signaling is an essential axis of osteoclast differentiation, Immunol. Rev. source
- cites [25] Takayanagi, 2007, The role of NFAT in osteoclast formation, Ann. N. Y. Acad. Sci. source
- cites [27] Shinohara, 2007, Novel osteoclast signaling mechanism, Curr. Osteoporos. Rep. source
- cites [23] Kobayashi, 2009, Action of RANKL and OPG for osteoclastogenesis, Crit. Rev. Eukaryot. Gene Expr. source
- cites [28] Takayanagi, 2005, Mechanistic insight into osteoclast differentiation in osteoimmunology, J. Mol. Med. source
May combine two claims.
PremisecitationIL-12 enhances the ability of IL-18 to inhibit TNF-α-mediated osteoclastogenesis, and the inhibition is T-cell independent.
“Using injections of TNF-α alone and with IL-18 or IL-18 + IL-12 into live murine supracalvaria, Morita and associates found that IL-12 enhanced IL-18s ability to inhibit TNF-α-mediated osteoclastogenesis and that the inhibition was T-cell independent [46].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Morita, 2010, IL-18 inhibits TNF-alpha-induced osteoclastogenesis possibly via a T cell-independent mechanism in synergy with IL-12 in vivo, Calcif. Tissue Int. source
May combine two claims.
PremisecitationIFN-γ directly inhibits TNF-α-mediated osteoclastogenesis and induces osteoclast precursor apoptosis by upregulating Fas/Fas ligand binding.
“Moreover, using cultures of murine bone marrow macrophages, Kohara and associates found that IFN-γ directly inhibited TNF-α-mediated osteoclastogenesis and induced osteoclast precursor apoptosis by upregulating Fas/Fas ligand binding [49] (Table 1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49] Kohara, 2011, IFN-γ directly inhibits TNF-α-induced osteoclastogenesis in vitro and in vivo and induces apoptosis mediated by Fas/Fas ligand interactions, Immunol. Lett. source
May combine two claims.
PremisecitationIn bioreactor cultures flown for 10 days on FOTON-M3, microgravity increased by several-fold the expression of genes involved in osteoclast activation and function, and osteoclast bone resorption was increased as evidenced by increases in collagen telopeptide production compared to ground controls.
“They found that microgravity increased by several-fold the expression of genes involved in osteoclast activation and function; osteoclast bone resorption was also increased as evidenced by increases in collagen telopeptide production as compared to that of ground controls [62].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [62] Tamma, 2009, Microgravity during spaceflight directly affects in vitro osteoclastogenesis and bone resorption, FASEB J. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIL-7 plus RANKL produced by activated T cells stimulates osteoclastogenesis in cultures of peripheral blood mononuclear cells.
“Moreover, IL-7 + RANKL produced by activated T cells is reported to stimulate osteoclastogenesis in cultures of peripheral blood mononuclear cells [37].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Salamanna, 2016, Peripheral blood mononuclear cells spontaneous osteoclastogenesis: Mechanisms driving the process and clinical relevance in skeletal disease, J. Cell Physiol. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIL-34 produced by osteoblasts recognizes the receptor for M-CSF (C-Fms) on osteoclast progenitors, thereby promoting osteoclastogenesis.
“IL-34 produced by osteoblasts recognizes the receptor for M-CSF (C-Fms) on osteoclast progenitors, thereby promoting osteoclastogenesis [38].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Guillonneau, 2017, Immunoregulatory properties of the cytokine IL-34, Cell Mol. Life Sci. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIL-17 produced by T17 lymphocytes serves as a potent osteoclastogenic cytokine in association with inflammatory joint diseases such as rheumatoid arthritis.
“In association with inflammatory joint diseases such as rheumatoid arthritis, IL-17 produced by T17 lymphocytes serves as a potent osteoclastogenic cytokine [1].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Okamoto, 2017, Osteoimmunology: The conceptual framework unifying the immune and skeletal systems, Physiol. Rev. source
May combine two claims.
PremisecitationSpaceflight osteoblasts had shorter and curvier microtubules, a reduced number and size of focal adhesins, and more condensed and fragmented nuclei compared to ground controls.
“The authors found that spaceflight osteoblasts had shorter and curvier microtubules, a reduced number and size of focal adhesins, and more condensed and fragmented nuclei when compared to ground controls, findings in keeping with other reports on the adverse effects of microgravity osteoblast cytoskeleton integrity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [54] Nabavi, 2011, Effects of microgravity on osteoclast bone resorption and osteoblast cytoskeletal organization and adhesion, Bone source
May combine two claims.
PremisecitationIn seven Wistar rats flown for seven days aboard BIOCOSMOS 1667, microgravity reduced tibial trabecular bone volume by 47-55%, trabecular thickness by 20-24%, and trabecular density by 40-43% compared to ground controls.
“Microgravity reduced tibial trabecular bone volume by 47–55%, trabecular thickness by 20–24%, and trabecular density by 40–43% as compared to ground controls.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [57] Vico, 1988, Trabecular bone remodeling after seven days of weightlessness exposure (BIOCOSMOS 1667), Am. J. Physiol. source
May combine two claims.
PremisecitationIn mice subjected to 1-18 days of 30° head-down tail suspension, osteocyte apoptosis occurred on day 3, followed by increased endosteal osteoclast numbers and resorptive activity and decreased bone density and compressive resistance at 18 days.
“They found evidence of osteocyte apoptosis on day 3 of suspension followed by increased endosteal levels of osteoclast numbers and resorptive activity and decreased bone density and compressive resistance at 18 days of tail suspension.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [64] Aguirre, 2006, Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss, J. Bone Miner. Res. source
May combine two claims.
InterpretationreasoningUnloading of bone on Earth and in the microgravity of space is associated with decreased bone formation and increased bone resorption.
“Unloading of bone on Earth and in the microgravity of space is associated with decreased bone formation and increased bone resorption.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSimulated gravity causes osteocyte apoptosis and consequent increases in levels of osteoclasts and osteoclast-mediated bone resorption.
“They concluded that simulated gravity causes osteocyte apoptosis and consequent increases in levels of osteoclasts and osteoclast-mediated bone resorption [64] (Figure 7).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [64] Aguirre, 2006, Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss, J. Bone Miner. Res. source
May combine two claims.
PremisecitationMonthly subcutaneous injections of romosozumab are effective in increasing bone formation and density and decreasing bone resorption.
“monthly subcutaneous injections of romosozumab are effective in increasing bone formation and density and decreasing bone resorption”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [73] Bandeira, 2017, Romosozumab for treatment of osteoporosis, Expert Opin. Biol. Ther. source
May combine two claims.
PremisecitationBisphosphonates inhibit the stimulatory activity of osteoclasts on osteoblast differentiation, and as a consequence, patients on these drugs suffer from a blockade of de novo bone formation.
“biphosphonates inhibit the stimulatory activity of osteoclasts on osteoblast differentiation and, as a consequence, patients on these drugs suffer from a blockade of de novo bone formation [12,70]”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationDenosumab has undesirable side effects and, similar to bisphosphonates, adversely affects osteoblastogenesis.
“denosumab, has been shown to have undesirable side effects and, similar to biphosphonates, adversely affects osteoblastogenesis [71]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [71] Deeks, 2018, Denosumab: A review in postmenopausal osteoporosis, Drugs Aging source
May combine two claims.
InterpretationreasoningAstronauts are at risk of losing bone mass and damaging joint cartilages despite NASA's efforts to protect their skeletal system by initiating exercise programs and nutritious diets.
“Astronauts are at risk of losing bone mass and damaging joint cartilages despite NASA’s efforts to protect their skeletal system by initiating exercise programs and nutritious diets.”
Quote in the paperSubstantial claim- Rests on an assumption: Simulated microgravity using the RWV is a valid model for actual microgravity conditions in space.
The paper relies on this without support.
Astronauts lose 1.0% to 1.5% of their bone mass for every month they spend in space despite adherence to diets and exercise regimens designed to protect their musculoskeletal systems.
“Astronauts are at risk of losing 1.0% to 1.5% of their bone mass for every month they spend in space despite their adherence to diets and exercise regimens designed to protect their musculoskeletal systems.”
The paper relies on this without support.
Astronauts experience traumatic joint injuries involving their knees, ankles, hips, and shoulders at almost three times the rate as individuals on Earth.
“In this regard, it is important to note that astronauts experience traumatic joint injuries involving their knees, ankles, hips, and shoulders at almost three times the rate as individuals on Earth.”
The paper relies on this without support.
Simulated microgravity using the RWV is a valid model for actual microgravity conditions in space.
“Using NASA’s Rotary Wall Vessel Bioreactor (RWV) and rotary cell cultures of RAW 264.7 osteoclast progenitor cells, Sambandam and associates found that simulated microgravity increased osteoclastogenesis by twofold”
The paper relies on this without support.
Calcitonin is an osteoclast-inhibiting hormone.
“Calcitonin is an osteoclast-inhibiting hormone, and, as previously noted, RANKL binding to RANK is required for osteoclastogenesis.”
The paper relies on this without support.
RANKL binding to RANK is required for osteoclastogenesis.
“Calcitonin is an osteoclast-inhibiting hormone, and, as previously noted, RANKL binding to RANK is required for osteoclastogenesis.”
The paper relies on this without support.
Astronauts experience an increased incidence of post-traumatic osteoarthritis involving their knees, ankles, hips, and shoulders.
“Because astronauts experience an increased incidence of post-traumatic osteoarthritis involving their knees, ankles, hips, and shoulders”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
BMP-1 in the text conflicts with the cited BMP-2 study
MinorThe text attributes the reported effect on osteoclasts to bone morphogenetic protein-1, but the cited reference [36] identifies the protein studied as bone morphogenic protein 2.
“Bone morphogenetic protein-1 in conjunction with RANKL has been shown to increase the differentiation and survival of osteoclasts [36].”
“36. Itoh K. Udagawa N. Takagiri T. Iemura S. Ueno N. Yasuda H. Higashio K. Quinn J.M. Gillespie M.T. Martin T.J. Bone morphogenic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kappaB ligand”
Cites
Role of proinflammatory cytokines in the pathophysiology of osteoarthritis
Kapoor, M., Martel-Pelletier, J., Lajeunesse, D., Pelletier, J.-P., & Fahmi, H. (2011) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2010.196 · Cited by 2,778 · see citing works
Lam, J., Takeshita, S., Barker, J. E., Kanagawa, O., Ross, F. P., & Teitelbaum, S. L. (2000) · Journal of Clinical Investigation · doi:10.1172/jci11176 · Cited by 1,440 · cited 1× · see citing works
“TNF-α induces osteoclastogenesis in RANKL and M-CSF positive hematopoietic cell precursors [29, 30] where its effects are mediated by TNF-α receptors type 1 (p55r) and type 2 (p75r), the former being the most effective in inducing the differentiation of TRAP-positive multinucleated cells [31].”
BackgroundThe molecular understanding of osteoclast differentiation
Asagiri, M., & Takayanagi, H. (2007) · Bone · doi:10.1016/j.bone.2006.09.023 · Cited by 1,363 · cited 1× · see citing works
“NFATc1 binds to its own promoter, switching on an epigenetically controlled autoregulatory cycle that permits efficient induction of the osteoclast-specific genes, tartrate-resistant acid phosphatase (TRAP), cathepsin K, as well as the fusion-specific genes, dendritic cell-specific transmembrane protein (DC-STAMP) and…”
BackgroundThe actin cytoskeleton and actin-based motility
Svitkina, T. (2018) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a018267 · Cited by 761 · cited 1× · see citing works
“This adaptation has involved the construction of cytoskeletons supported by actin and intermediate filaments and microtubules [2,3], intracellular adhesion molecules including integrins and cell extension kinases [4,5], plasma membrane and nuclear mechanosensors [6], and thermal convection currents which renew nutrien…”
BackgroundTumor Necrosis Factor-α Induces Differentiation of and Bone Resorption by Osteoclasts
Azuma, Y., Kaji, K., Katogi, R., Takeshita, S., & Kudo, A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.7.4858 · Cited by 731 · see citing works
Regulation of NFATc1 in Osteoclast Differentiation
Kim, J. H., & Kim, N. (2014) · Journal of Bone Metabolism · doi:10.11005/jbm.2014.21.4.233 · Cited by 570 · cited 3× · see citing works
“NFATc1 binds to its own promoter, switching on an epigenetically controlled autoregulatory cycle that permits efficient induction of the osteoclast-specific genes, tartrate-resistant acid phosphatase (TRAP), cathepsin K, as well as the fusion-specific genes, dendritic cell-specific transmembrane protein (DC-STAMP) and…”
BackgroundInhibition of Osteoblast Differentiation by Tumor Necrosis Factor-α*
Gilbert, L., He, X., Farmer, P., Boden, S., Kozlowski, M., Rubin, J., & Nanes, M. S. (2000) · Endocrinology · doi:10.1210/endo.141.11.7739 · Cited by 555 · see citing works
Osteoimmunology: The conceptual framework unifying the immune and skeletal systems
Okamoto, K., Nakashima, T., Shinohara, M., Negishi-Koga, T., Komatsu, N., Terashima, A., Sawa, S., Nitta, T., & Takayanagi, H. (2017) · Physiological Reviews · doi:10.1152/physrev.00036.2016 · Cited by 534 · cited 2× · see citing works
“This osteoimmunological system is complex and involves commonly shared osteoclastogenic factors such as receptor activator of the nuclear factor-kappa B (NF-κB) ligand and macrophage colony stimulating factor as well as cytokines and immune cells that inhibit or enhance osteoclast ontogeny [1].”
BackgroundSphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis
Ishii, M., Egen, J. G., Klauschen, F., Meier-Schellersheim, M., Saeki, Y., Vacher, J., Proia, R. L., & Germain, R. N. (2009) · Nature · doi:10.1038/nature07713 · Cited by 515 · cited 3× · see citing works
“Bone marrow osteoclast hematopoietic stem cells (HSCs) expressing type-2 receptor for sphingosine-1-phosphate (S1PR2) enter the circulation by binding sphingosine-1-phosphate (S1P), a chemotactic lysophospholipid normally present in high concentrations in blood [15,16].”
BackgroundAguirre, J. I., Plotkin, L. I., Stewart, S. A., Weinstein, R. S., Parfitt, A. M., Manolagas, S. C., & Bellido, T. (2006) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.060107 · Cited by 494 · see citing works
Advances in the regulation of osteoclasts and osteoclast functions
Boyce, B. F. (2013) · Journal of Dental Research · doi:10.1177/0022034513500306 · Cited by 457 · cited 16× · see citing works
“1), heterodimeric complex of microphthalmia-associated transcription factor (MITF), and transcription factor E3 (TfE3), which initiate the expression of the colony stimulating factor-1 receptor (C-Fms) [18].”
BackgroundInfluentialThe role of NFAT in osteoclast formation
TAKAYANAGI, H. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1402.071 · Cited by 442 · cited 2× · see citing works
“NFATc1 binds to its own promoter, switching on an epigenetically controlled autoregulatory cycle that permits efficient induction of the osteoclast-specific genes, tartrate-resistant acid phosphatase (TRAP), cathepsin K, as well as the fusion-specific genes, dendritic cell-specific transmembrane protein (DC-STAMP) and…”
BackgroundCa <sup>2+</sup> ‐NFATc1 signaling is an essential axis of osteoclast differentiation
Negishi‐Koga, T., & Takayanagi, H. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00821.x · Cited by 415 · cited 2× · see citing works
“This activates cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and the calcineurin pathway [21,24,25,27], a key costimulatory pathway of NFATc1 [21,23] and an important signaling component of a number of immune cell receptors [28] (Figures 4 and 5).”
BackgroundMechanistic insight into osteoclast differentiation in osteoimmunology
Takayanagi, H. (2005) · Journal of Molecular Medicine · doi:10.1007/s00109-004-0612-6 · Cited by 413 · cited 1× · see citing works
“This activates cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and the calcineurin pathway [21,24,25,27], a key costimulatory pathway of NFATc1 [21,23] and an important signaling component of a number of immune cell receptors [28] (Figures 4 and 5).”
BackgroundUdagawa, N., Horwood, N. J., Elliott, J., Mackay, A., Owens, J., Okamura, H., Kurimoto, M., Chambers, T. J., Martin, T. J., & Gillespie, M. T. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.185.6.1005 · Cited by 378 · see citing works
Transforming Growth Factor β Affects Osteoclast Differentiation via Direct and Indirect Actions
Quinn, J. M. W., Itoh, K., Udagawa, N., Häusler, K., Yasuda, H., Shima, N., Mizuno, A., Higashio, K., Takahashi, N., Suda, T., et al. (2001) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2001.16.10.1787 · Cited by 278 · see citing works
Review: Bone tissue engineering: The role of interstitial fluid flow
Hillsley, M. V., & Frangos, J. A. (1994) · Biotechnology and Bioengineering · doi:10.1002/bit.260430706 · Cited by 270 · see citing works
Itoh, K., Udagawa, N., Katagiri, T., Iemura, S., Ueno, N., Yasuda, H., Higashio, K., Quinn, J. M. W., Gillespie, M. T., Martin, T. J., et al. (2001) · Endocrinology · doi:10.1210/endo.142.8.8300 · Cited by 250 · see citing works
IL-12 Alone and in Synergy with IL-18 Inhibits Osteoclast Formation In Vitro
Horwood, N. J., Elliott, J., Martin, T. J., & Gillespie, M. T. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.8.4915 · Cited by 248 · cited 1× · see citing works
“Horwood and associates also reported that IL-12 inhibited osteoclast formation in vitro [47].”
BackgroundBisphosphonates as a supplement to exercise to protect bone during long-duration spaceflight
LeBlanc, A., Matsumoto, T., Jones, J., Shapiro, J., Lang, T., Shackelford, L., Smith, S. M., Evans, H., Spector, E., Ploutz-Snyder, R., et al. (2013) · Osteoporosis International · doi:10.1007/s00198-012-2243-z · Cited by 234 · see citing works
FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions
Tapial Martínez, P., López Navajas, P., & Lietha, D. (2020) · Biomolecules · doi:10.3390/biom10020179 · Cited by 206 · see citing works
Wei, S., Wang, M. W.-H., Teitelbaum, S. L., & Ross, F. P. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m104957200 · Cited by 202 · cited 16× · see citing works
“This loss was associated with an upregulation in osteoclastogenesis-related signaling molecules ERK, p38, PLCγ2, and NFATc1 and osteoclast-specific markers TRAP and cathepsin K.”
BackgroundInfluentialBlaber, E. A., Dvorochkin, N., Lee, C., Alwood, J. S., Yousuf, R., Pianetta, P., Globus, R. K., Burns, B. P., & Almeida, E. A. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061372 · Cited by 196 · see citing works
Kitaura, H., Sands, M. S., Aya, K., Zhou, P., Hirayama, T., Uthgenannt, B., Wei, S., Takeshita, S., Novack, D. V., Silva, M. J., et al. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.8.4838 · Cited by 190 · see citing works
Cappellen, D., Luong-Nguyen, N.-H., Bongiovanni, S., Grenet, O., Wanke, C., & Šuša, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200434200 · Cited by 184 · cited 2× · see citing works
“M-CSF ligation also initiates the expression of several cytokines and their receptors including interleukin (IL)-1α, IL-18, interferon (IFN)-β, IL-11Rα2, IL-6/11R gp130, and IFN-γ-R; also expressed are factors involved in the cell’s response to RANKL ligation, including tumor necrosis factor receptor-associated factor…”
BackgroundAction of RANKL and OPG for Osteoclastogenesis
Kobayashi, Y., Udagawa, N., & Takahashi, N. (2009) · Critical Reviews™ in Eukaryotic Gene Expression · doi:10.1615/critreveukargeneexpr.v19.i1.30 · Cited by 176 · cited 2× · see citing works
“This activates cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and the calcineurin pathway [21,24,25,27], a key costimulatory pathway of NFATc1 [21,23] and an important signaling component of a number of immune cell receptors [28] (Figures 4 and 5).”
BackgroundNabavi, N., Khandani, A., Camirand, A., & Harrison, R. E. (2011) · Bone · doi:10.1016/j.bone.2011.07.036 · Cited by 174 · see citing works
Denosumab: A review in postmenopausal osteoporosis
Deeks, E. D. (2018) · Drugs & Aging · doi:10.1007/s40266-018-0525-7 · Cited by 169 · see citing works
Function of the cytoskeleton in gravisensing during spaceflight
Hughes‐Fulford, M. (2003) · Advances in Space Research · doi:10.1016/s0273-1177(03)90399-1 · Cited by 149 · see citing works
Zhao, B., & Ivashkiv, L. B. (2011) · Arthritis Research & Therapy · doi:10.1186/ar3379 · Cited by 144 · see citing works
(2005) · PubMed · Cited by 135 · see citing works
TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation
Lamothe, B., Webster, W. K., Gopinathan, A., Besse, A., Campos, A. D., & Darnay, B. G. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.06.017 · Cited by 134 · see citing works
Gerbaix, M., Gnyubkin, V., Farlay, D., Olivier, C., Ammann, P., Courbon, G., Laroche, N., Genthial, R., Follet, H., Peyrin, F., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-03014-2 · Cited by 127 · see citing works
Tamma, R., Colaianni, G., Camerino, C., Di Benedetto, A., Greco, G., Strippoli, M., Vergari, R., Grano, A., Mancini, L., Mori, G., et al. (2009) · The FASEB Journal · doi:10.1096/fj.08-127951 · Cited by 121 · see citing works
Mohamed, S. G.-K., Sugiyama, E., Shinoda, K., Taki, H., Hounoki, H., Abdel-Aziz, H. O., Maruyama, M., Kobayashi, M., Ogawa, H., & Miyahara, T. (2007) · Bone · doi:10.1016/j.bone.2007.05.016 · Cited by 120 · cited 15× · see citing works
“This loss was associated with an upregulation in osteoclastogenesis-related signaling molecules ERK, p38, PLCγ2, and NFATc1 and osteoclast-specific markers TRAP and cathepsin K.”
BackgroundInfluentialInterventions to prevent bone loss in astronauts during space flight
Iwamoto, J., Takeda, T., & Sato, Y. (2005) · The Keio Journal of Medicine · doi:10.2302/kjm.54.55 · Cited by 114 · cited 1× · see citing works
“5% of their bone mass for every month they spend in space despite their adherence to high impact exercise programs and diets high in nutrients, potassium, calcium, and vitamin D, all designed to preserve the skeletal system [9-13].”
BackgroundImmunoregulatory properties of the cytokine IL-34
Guillonneau, C., Bézie, S., & Anegon, I. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2482-4 · Cited by 112 · cited 1× · see citing works
“IL-34 produced by osteoblasts recognizes the receptor for M-CSF (C-Fms) on osteoclast progenitors, thereby promoting osteoclastogenesis [38].”
BackgroundRucci, N., Rufo, A., Alamanou, M., & Teti, A. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21059 · Cited by 108 · see citing works
Tanabe, N., Maeno, M., Suzuki, N., Fujisaki, K., Tanaka, H., Ogiso, B., & Ito, K. (2005) · Life Sciences · doi:10.1016/j.lfs.2004.10.079 · Cited by 103 · see citing works
Romosozumab for the treatment of osteoporosis
Bandeira, L., Lewiecki, E. M., & Bilezikian, J. P. (2017) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2017.1280455 · Cited by 101 · see citing works
Trabecular bone remodeling after seven days of weightlessness exposure (BIOCOSMOS 1667)
Vico, L., Chappard, D., Palle, S., Bakulin, A. V., Novikov, V. E., & Alexandre, C. (1988) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1988.255.2.r243 · Cited by 99 · see citing works
Microgravity control of autophagy modulates osteoclastogenesis
Sambandam, Y., Townsend, M. T., Pierce, J. J., Lipman, C. M., Haque, A., Bateman, T. A., & Reddy, S. V. (2014) · Bone · doi:10.1016/j.bone.2014.01.004 · Cited by 93 · see citing works
Melatonin is a potential drug for the prevention of bone loss during space flight
Ikegame, M., Hattori, A., Tabata, M. J., Kitamura, K., Tabuchi, Y., Furusawa, Y., Maruyama, Y., Yamamoto, T., Sekiguchi, T., Matsuoka, R., et al. (2019) · Journal of Pineal Research · doi:10.1111/jpi.12594 · Cited by 89 · see citing works
Effects of cyclic hydraulic pressure on osteocytes
Liu, C., Zhao, Y., Cheung, W.-Y., Gandhi, R., Wang, L., & You, L. (2010) · Bone · doi:10.1016/j.bone.2010.02.006 · Cited by 88 · see citing works
Space Flight Calcium: Implications for Astronaut Health, Spacecraft Operations, and Earth
Smith, S., McCoy, T., Gazda, D., Morgan, J., Heer, M., & Zwart, S. (2012) · Nutrients · doi:10.3390/nu4122047 · Cited by 85 · see citing works
Integrin and microtubule crosstalk in the regulation of cellular processes
LaFlamme, S. E., Mathew-Steiner, S., Singh, N., Colello-Borges, D., & Nieves, B. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2913-x · Cited by 84 · cited 1× · see citing works
“This adaptation has involved the construction of cytoskeletons supported by actin and intermediate filaments and microtubules [2,3], intracellular adhesion molecules including integrins and cell extension kinases [4,5], plasma membrane and nuclear mechanosensors [6], and thermal convection currents which renew nutrien…”
BackgroundSaxena, R., Pan, G., Dohm, E. D., & McDonald, J. M. (2011) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-010-0201-4 · Cited by 80 · see citing works
The osteoclast cytoskeleton – current understanding and therapeutic perspectives for osteoporosis
Blangy, A., Bompard, G., Guerit, D., Marie, P., Maurin, J., Morel, A., & Vives, V. (2020) · Journal of Cell Science · doi:10.1242/jcs.244798 · Cited by 76 · see citing works
Kohara, H., Kitaura, H., Fujimura, Y., Yoshimatsu, M., Morita, Y., Eguchi, T., Masuyama, R., & Yoshida, N. (2011) · Immunology Letters · doi:10.1016/j.imlet.2011.02.017 · Cited by 75 · cited 1× · see citing works
“Moreover, using cultures of murine bone marrow macrophages, Kohara and associates found that IFN-γ directly inhibited TNF-α-mediated osteoclastogenesis and induced osteoclast precursor apoptosis by upregulating Fas/Fas ligand binding [49] (Table 1).”
BackgroundHistomorphometric analyses of cancellous bone from COSMOS 2044 rats
Vico, L., Bourrin, S., Genty, C., Palle, S., & Alexandre, C. (1993) · Journal of Applied Physiology · doi:10.1152/jappl.1993.75.5.2203 · Cited by 72 · see citing works
Novel osteoclast signaling mechanisms
Shinohara, M., & Takayanagi, H. (2007) · Current Osteoporosis Reports · doi:10.1007/s11914-007-0005-1 · Cited by 72 · see citing works
Kitaura, H., Nagata, N., Fujimura, Y., Hotokezaka, H., Yoshida, N., & Nakayama, K. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.9.4732 · Cited by 72 · cited 1× · see citing works
“Using mouse bone marrow cultures, Kitaura and associates found that IL-12 when added to TNF-α-stimulated cultures induced osteoclast apoptosis by upregulating their expression of Fas/Fas ligands [45].”
BackgroundVico, L., Chappard, D., Alexandre, C., Palle, S., Minaire, P., Riffat, G., Novikov, V. E., & Bakulin, A. V. (1987) · Bone · doi:10.1016/8756-3282(87)90077-9 · Cited by 69 · see citing works
Osteoprotegerin is an effective countermeasure for spaceflight-induced bone loss in mice
Lloyd, S. A., Morony, S. E., Ferguson, V. L., Simske, S. J., Stodieck, L. S., Warmington, K. S., Livingston, E. W., Lacey, D. L., Kostenuik, P. J., & Bateman, T. A. (2015) · Bone · doi:10.1016/j.bone.2015.08.021 · Cited by 68 · see citing works
Stone, J. A., McCrea, J. B., Witter, R., Zajic, S., & Stoch, S. A. (2019) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.13869 · Cited by 66 · see citing works
Fujii, T., Kitaura, H., Kimura, K., Hakami, Z., & Takano-Yamamoto, T. (2012) · Bone · doi:10.1016/j.bone.2012.06.024 · Cited by 64 · see citing works
Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do?
Vargas‐Franco, J. W., Castaneda, B., Rédiní, F., Gómez, D. F., Heymann, D., & Lézot, F. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26465 · Cited by 64 · see citing works
Microarray profile of gene expression during osteoclast differentiation in modelled microgravity
Sambandam, Y., Blanchard, J. J., Daughtridge, G., Kolb, R. J., Shanmugarajan, S., Pandruvada, S. N. M., Bateman, T. A., & Reddy, S. V. (2010) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22840 · Cited by 62 · see citing works
SOST/Sclerostin improves posttraumatic osteoarthritis and inhibits MMP2/3 expression after injury
Chang, J. C., Christiansen, B. A., Murugesh, D. K., Sebastian, A., Hum, N. R., Collette, N. M., Hatsell, S., Economides, A. N., Blanchette, C. D., & Loots, G. G. (2018) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3397 · Cited by 58 · see citing works
IL-6 and the dysregulation of immune, bone, muscle, and metabolic homeostasis during spaceflight
Smith, J. K. (2018) · npj Microgravity · doi:10.1038/s41526-018-0057-9 · Cited by 56 · see citing works
Self-citationRegulation of CXCL12 expression by canonical Wnt signaling in bone marrow stromal cells
Tamura, M., Sato, M. M., & Nashimoto, M. (2011) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2011.01.021 · Cited by 51 · cited 2× · see citing works
“Circulating CXCR4-expressing HSCs are attracted to bone surfaces by gradients of SDF-1 (CXCL12) secreted by CXCR4+ CD45−, stromal, and endothelial marrow cells [14,17].”
BackgroundKamel Mohamed, S. G., Sugiyama, E., Shinoda, K., Hounoki, H., Taki, H., Maruyama, M., Miyahara, T., & Kobayashi, M. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.02.049 · Cited by 51 · see citing works
Chatani, M., Morimoto, H., Takeyama, K., Mantoku, A., Tanigawa, N., Kubota, K., Suzuki, H., Uchida, S., Tanigaki, F., Shirakawa, M., et al. (2016) · Scientific Reports · doi:10.1038/srep39545 · Cited by 50 · see citing works
The Role of Sclerostin in Bone and Ectopic Calcification
De Maré, A., D’Haese, P. C., & Verhulst, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093199 · Cited by 45 · see citing works
Morita, Y., Kitaura, H., Yoshimatsu, M., Fujimura, Y., Kohara, H., Eguchi, T., & Yoshida, N. (2010) · Calcified Tissue International · doi:10.1007/s00223-010-9335-6 · Cited by 39 · see citing works
Chain reaction: LINC complexes and nuclear positioning
Burke, B. (2019) · F1000Research · doi:10.12688/f1000research.16877.1 · Cited by 35 · cited 2× · see citing works
“The cytoskeleton fulfills essential functions including cell adhesion, migration, contractility, division, vesicular transport, and bone resorption [2-6].”
BackgroundShakeri, A., & Adanty, C. (2020) · Journal of Population Therapeutics & Clinical Pharmacology · doi:10.15586/jptcp.v27i1.655 · Cited by 35 · see citing works
Ishii, T., Shimazu, Y., Nishiyama, I., Kikuta, J., & Ishii, M. (2011) · Molecules and Cells · doi:10.1007/s10059-011-1010-x · Cited by 32 · see citing works
Sambandam, Y., Baird, K. L., Stroebel, M., Kowal, E., Balasubramanian, S., & Reddy, S. V. (2016) · Scientific Reports · doi:10.1038/srep25143 · Cited by 31 · see citing works
Microgravity modulation of syncytin-A expression enhance osteoclast formation
Ethiraj, P., Link, J. R., Sinkway, J. M., Brown, G. D., Parler, W. A., & Reddy, S. V. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26750 · Cited by 30 · see citing works
Zawawi, M. S. F., Dharmapatni, A. A. S. S. K., Cantley, M. D., McHugh, K. P., Haynes, D. R., & Crotti, T. N. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.09.077 · Cited by 29 · see citing works
Goto, Y., Aoyama, M., Sekiya, T., Kakita, H., Waguri-Nagaya, Y., Miyazawa, K., Asai, K., & Goto, S. (2016) · Stem Cells · doi:10.1002/stem.2440 · Cited by 27 · see citing works
Cytoplasmic convection currents and intracellular temperature gradients
Howard, R., Scheiner, A., Cunningham, J. J., & Gatenby, R. A. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1007372 · Cited by 27 · cited 1× · see citing works
“This adaptation has involved the construction of cytoskeletons supported by actin and intermediate filaments and microtubules [2,3], intracellular adhesion molecules including integrins and cell extension kinases [4,5], plasma membrane and nuclear mechanosensors [6], and thermal convection currents which renew nutrien…”
BackgroundSalamanna, F., Maglio, M., Borsari, V., Giavaresi, G., Aldini, N. N., & Fini, M. (2016) · Journal of Cellular Physiology · doi:10.1002/jcp.25134 · Cited by 23 · cited 1× · see citing works
“Moreover, IL-7 + RANKL produced by activated T cells is reported to stimulate osteoclastogenesis in cultures of peripheral blood mononuclear cells [37].”
BackgroundHonda, K. (2011) · Journal of Oral Science · doi:10.2334/josnusd.53.87 · Cited by 15 · see citing works
Watanabe, Y., Namba, A., Aida, Y., Honda, K., Tanaka, H., Suzuki, N., Matsumura, H., & Maeno, M. (2009) · Mediators of Inflammation · doi:10.1155/2009/308596 · Cited by 13 · see citing works
Microgravity, Bone Homeostasis, and Insulin-Like Growth Factor-1
Smith, J. K. (2020) · Applied Sciences · doi:10.3390/app10134433 · Cited by 12 · see citing works
Self-citationMicrogravity, Bone Homeostasis, and Insulin-like Growth Factor-1
Smith, J. K. (2020) · doi:10.20944/preprints202005.0293.v1 · Cited by 12
Self-citation
Flagged first, then by citations
1 of the 79 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Genah, S., Monici, M., & Morbidelli, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094585 · Cited by 77 · see citing works
May the Force Be with You (Or Not): The Immune System under Microgravity
ElGindi, M., Sapudom, J., Ibrahim, I. H., Al‐Sayegh, M., Chen, W., Garcia‐Sabaté, A., & Teo, J. C. M. (2021) · Cells · doi:10.3390/cells10081941 · Cited by 72 · see citing works
The role of sphingosine-1-phosphate in bone remodeling and osteoporosis
Grewe, J. M., Knapstein, P., Donat, A., Jiang, S., Smit, D. J., Xie, W., & Keller, J. (2022) · Bone Research · doi:10.1038/s41413-022-00205-0 · Cited by 68 · see citing works
Biomanufacturing in low Earth orbit for regenerative medicine
Sharma, A., Clemens, R. A., Garcia, O., Taylor, D. L., Wagner, N. L., Shepard, K. A., Gupta, A. E., Malany, S., Grodzinsky, A. J., Kearns‐Jonker, M., et al. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.12.001 · Cited by 54 · see citing works
“Stem This is an open access arti result in effects including cardiovascular deconditioning, skeletal muscle atrophy, bone loss, and immune dysfunction, among others (Patel, 2020; Shelhamer et al., 2020; Smith, 2020; Vernikos and Schneider, 2010).”
BackgroundLau, P., Vico, L., & Rittweger, J. (2022) · Biomedicines · doi:10.3390/biomedicines10020342 · Cited by 32 · see citing works
“In blunt contrast, to the negative impact of weightlessness on osteoblasts [55], in which the cytoskeleton collapses from the failure of microtubules and actin filaments, for the osteoclasts their ability to resorb bone in microgravity is still maintained [70].”
BackgroundLi, Y., Liu, S., Liu, H., Cui, Y., & Deng, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052722 · Cited by 26 · see citing works
Cao, S., Wang, Y., Zhang, Y., Ren, J., Fan, B., Deng, Y., & Yin, W. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c05370 · Cited by 23 · see citing works
Ren, Z., Harriot, A. D., Mair, D. B., Chung, M. K., Lee, P. H. U., & Kim, D. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202300157 · Cited by 18 · see citing works
Wang, H., Liu, H., Wang, X., et al. (2021) · Life Sciences in Space Research · doi:10.1016/j.lssr.2021.09.002 · Cited by 18 · see citing works
Study on mass transfer in the bone lacunar-canalicular system under different gravity fields
Wang, H., Gao, L., Chen, X., et al. (2022) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-022-01373-z · Cited by 17 · see citing works
“Osteocytes communicate with other osteocytes, osteoblasts, and osteoclasts through the LCS in the bone matrix [11].”
BackgroundAn introduction to space medicine and the physiological effects of spaceflight on the human body
Ong, J., & Lee, A. G. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-91524-3.00007-7 · Cited by 14 · see citing works
Wu, Z., Hu, L., Ru, K., et al. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154745 · Cited by 14 · see citing works
Yamamoto, T., Ikegame, M., Furusawa, Y., et al. (2022) · ZOOLOGICAL SCIENCE · doi:10.2108/zs210107 · Cited by 12 · see citing works
“Interestingly, our ground basis results by simulated g-μG were mostly consistent with those of our space experiment (Ikegame et al., 2019; Smith, 2020).”
BackgroundResultInfluentialCarvajal-Agudelo, J. D., McNeil, A., & Franz‐Odendaal, T. A. (2023) · Life Sciences in Space Research · doi:10.1016/j.lssr.2023.05.002 · Cited by 10 · see citing works
Modeled microgravity unravels the roles of mechanical forces in renal progenitor cell physiology
Melica, M. E., Cialdai, F., Regina, G. L., et al. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-03633-3 · Cited by 9 · see citing works
Chen, Z., Xie, J., Ma, C., Zhang, P., & Lei, X. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26104583 · Cited by 10 · see citing works
“On a cellular level, microgravity inhibits osteoblast function, while osteoclasts are relatively more active and their mediated bone resorption is enhanced [4,5].”
Hu, M., Li, W., Yin, Q., Liu, Y., Chen, L., Ru, Q., Xu, G., & Wu, Y. (2025) · npj Microgravity · doi:10.1038/s41526-025-00515-7 · Cited by 9 · see citing works
AOP Report: Development of an adverse outcome pathway for deposition of energy leading to bone loss
Sandhu, S., Keyworth, M., Karimi‐Jashni, S., Alomar, D., Smith, B. J., Kozbenko, T., Doty, S. B., Hocking, R., Hamada, N., Reynolds, R. J., et al. (2024) · Environmental and Molecular Mutagenesis · doi:10.1002/em.22631 · Cited by 9 · see citing works
Macrophages Characterization in an Injured Bone Tissue
Nikovics, K., Durand, M., Castellarin, C., Burger, J., Sicherre, E., Collombet, J., Oger, M., Holy, X., & Favier, A. (2022) · Biomedicines · doi:10.3390/biomedicines10061385 · Cited by 8 · see citing works
The effect of different gravity fields on mass transfer in the rat bone lacunar-canalicular system
Wang, H., Wang, J., Li, K., et al. (2023) · Medicine in Novel Technology and Devices · doi:10.1016/j.medntd.2023.100208 · Cited by 8 · see citing works
Oral Health of Astronauts in Short- and Long-Term Missions in Space
FABBRO, M. D., Khijmatgar, S., Vandenberghe, B., Kijak, E., Kulesa-Mrowiecka, M., Singhal, I., Lorusso, F., Xavier, B. B., Sampson, V., Marfia, G., et al. (2025) · Aerospace Medicine and Human Performance · doi:10.3357/amhp.6372.2025 · Cited by 8 · see citing works
Sonawane, R., Patil, S., Rahaman, J., & Mukherjee, D. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152055 · Cited by 7 · see citing works
Opportunities for Biomanufacturing in Low Earth Orbit: Current Status and Future DirectionsPreprint
Giulianotti, M. A., Sharma, A., Clemens, R. A., Garcia, O., Taylor, L., Wagner, N. L., Shepard, K. A., Gupta, A., Malany, S., Grodzinsky, A. J., et al. (2021) · Preprints.org · doi:10.20944/preprints202108.0044.v1 · Cited by 6 · see citing works
Cahill, R., Blaber, E. A., Juran, C. M., Cheng-Campbell, M., Alwood, J. S., Shirazi‐Fard, Y., & Almeida, E. A. C. (2025) · PLoS ONE · doi:10.1371/journal.pone.0317307 · Cited by 6 · see citing works
“These effects are thought to be caused throughout bone tissue as a result of cellular proliferation and differentiation homeostasis imbalance between bone forming osteoblasts and bone degrading osteoclasts [30] with osteocytic osteolysis [31] and apoptosis [32] also playing a role.”
Pintus, G., Akram, M. A., Giordo, R., Caggiari, G., & Majdalawieh, A. F. (2025) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2025.11.048 · Cited by 8 · see citing works
Cohen, O. E., Neuman, S., Natan, Y., et al. (2024) · Life Sciences in Space Research · doi:10.1016/j.lssr.2024.02.007 · Cited by 6 · see citing works
Receptors Implicated in Microgravity-Induced Bone Loss
Martinez, E. F., Pelegrine, A. A., & Holliday, L. S. (2024) · Receptors · doi:10.3390/receptors3020014 · Cited by 4 · see citing works
Zhang, S., Ueno, D., Ohira, T., Kato, H., Izawa, T., Yamanouchi, S., Yoshida, Y., Takahashi, A., & Ohira, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.707470 · Cited by 4 · see citing works
“Some previous studies have found that partial gravity can promote osteoclast production and activity (Vico et al., 1993; Tamma et al., 2009; Blaber et al., 2013; Chatani et al., 2016; Smith, 2020; Stavnichuk et al., 2020).”
BackgroundCaruso, J. F., Patel, N., Wellwood, J., & Bollinger, L. M. (2023) · Aerospace Medicine and Human Performance · doi:10.3357/amhp.6255.2023 · Cited by 3 · see citing works
Using functionally characterized networks in the application of precision medicine in spaceflight
Schmidt, M. A., & Schmidt, J. C. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-13850-8.00018-x · Cited by 2 · see citing works
Exploring ageing in microgravity
ElGindi, M., & Teo, J. C. M. (2025) · Nature Reviews Bioengineering · doi:10.1038/s44222-025-00309-2 · Cited by 2 · see citing works
Clemente-Villalba, J., & Cerdá-Bernad, D. (2025) · Applied Sciences · doi:10.3390/app15169220 · Cited by 3 · see citing works
Han, S., & Kim, Y.-K. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178707 · Cited by 2 · see citing works
“Once in the nucleus, NFATc1 activates an osteoclast gene program that includes OSCAR , ATP6V0D2 , ACP5 (TRAP), OC-STAMP , DC-STAMP , CTSK , CALCR , and MMP-9 , supporting osteoclast differentiation, fusion, and bone resorption [23,39].”
InfluentialTosi, D. D., Tiberio, F., Pietro, L. D., Polito, L., Parolini, O., Minotti, A., Arcovito, A., & Lattanzi, W. (2026) · npj Microgravity · doi:10.1038/s41526-025-00556-y · Cited by 3 · see citing works
“Themaineffectof μ Gonboneisareductionofbonemass,suggestinga direct in fl uence on osteoclastogenesis 96 and osteoblastogenesis 97 .”
Zhang, Y., Di, C., Wang, N., et al. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-96123-3.00009-9 · Cited by 2 · see citing works
Interaction Network Provides Clues on the Role of BCAR1 in Cellular Response to Changes in Gravity
Bauer, J. W., Gombocz, E., Schulz, H., et al. (2021) · Computation · doi:10.3390/computation9080081 · Cited by 2 · see citing works
Chen, X., Yang, J., Lv, H., Che, J., Wang, J., Zhang, B., & Shang, P. (2022) · Acta Astronautica · doi:10.1016/j.actaastro.2022.10.020 · Cited by 2 · see citing works
Simulated microgravity increases CD226 + Lin−CD117−Sca1 + mesenchymal stem cells in mice
Zhou, W., Li, Y., Hou, Y., Dan, W., Chen, L., Shi, F., Zhao, F., & Fang, L. (2024) · Physiological Reports · doi:10.14814/phy2.15971 · Cited by 2 · see citing works
“Among them, bone loss induced by microgravity is due to the imbalance of bone related cells, especially osteoblasts, osteoclasts and MSCs (Baran et al., 2022; Iandolo et al., 2021; Smith, 2020).”
BackgroundSpace, the Final Frontier to Exploit and Annihilate: Space Exploration, Inhabitation and Settlement
Eski, Y. (2023) · Springer eBooks · doi:10.1007/978-3-031-36092-3_6 · Cited by 1 · see citing works
Progress in Prevention and Treatment of Acute Bone Loss in Orthopedics
Wang, H., Wu, J., Wang, B., Qin, H., Fan, L., Wang, Y.-H., & He, B. (2023) · International Journal of Endocrinology · doi:10.1155/2023/9373043 · Cited by 1 · see citing works
“Te common causes of acute bone loss are as follows [1, 5, 15–18]: (1) acute braking or plaster fxation caused by fracture and trauma; (2) stress reduction and periprosthetic infammation caused by joint replacement; (3) spinal cord injury; (4) weightlessness; and (5) conservative treatment of…”
BackgroundGordienko, K. V., Lukicheva, N. A., Akhmetzyanova, A., Kolupaev, A. K., Александрович, С. О., Baltina, T., Садчикова, Е. Р., & Vassilieva, G. Y. (2024) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s0022093024040306 · Cited by 1 · see citing works
Gordienko, K. V., Lukicheva, N. A., Akhmetzyanova, A., Kolupaev, A. K., Александрович, С. О., Baltina, T., Садчикова, Е. Р., & Vassilieva, G. Y. (2024) · Российский физиологический журнал им И М Сеченова · doi:10.31857/s0869813924080035 · Cited by 1 · see citing works
Space Travel and the Musculoskeletal System
Sharma, S., Banga, N., Sharma, A., et al. (2024) · Advances in medical diagnosis, treatment, and care (AMDTC) book series · doi:10.4018/979-8-3693-6869-5.ch010 · Cited by 1 · see citing works
The Mass Transfer Within the Lacunar-canalicular System of Rats Under Simulated Microgravity
Xiong, B., Liu, B., Wang, X., Ye, J., Gao, L., Li, X., & Zhang, C. (2025) · Microgravity Science and Technology · doi:10.1007/s12217-025-10206-3 · Cited by 1 · see citing works
“…activate cel - lular mechanical signaling pathways, but also effectively transports oxygen, metabolic waste and signaling molecules, thereby maintaining the activity and communication of osteocytes (Klein-Nulend et al. 2013; Ren et al. 2015; Kufahl and Saha 1990; Moriishi et al. 2012; Smith 2020).”
Lentini, V., Uras, G., Manca, A., Faqir, M. A. E., Pozo, S. L. D., Deiana, N., Cao, G., Schapira, A. H. V., & Pantaleo, A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.25.620204 · Cited by 1 · see citing works
“Microgravity profoundly affects biological systems, from single cells to entire organisms and cellular adjustment in these conditions can help the exploration of diverse pathophysiological processes [40–48].”
BackgroundMimic Spaceflight: Microgravity Induces Bone Injury
Zhang, W. (2023) · Highlights in Science Engineering and Technology · doi:10.54097/hset.v36i.6207
Caswell, G. M. (2024) · International Journal of Geriatrics and Gerontology · doi:10.29011/2577-0748.100075
Yang, S., Chen, M., Yang, D., Deng, F., & Guo, X. (2025) · Archives of Toxicology · doi:10.1007/s00204-025-04265-z
Yu, M., Wang, X., Gu, X., Luan, J. Y., Huang, J., Sun, W., Yuan, X., Cao, S., Pan, J., Mao, T., et al. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.153598 · Cited by 1 · see citing works
The link between body heat accrual and cognition: future considerations for in-flight exercise
Wydotis, M. M., Stocke, S., Rapp, L., Bradley, K., Bollinger, L. M., & Caruso, J. F. (2026) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00035.2026
The “osteostat”: a theory of bone mechanosensing and setpoint adaptation based on osteocytesPreprint
Pauchard, Y., & Buenzli, P. R. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.23.734120
“However, osteocyte decrease in unloading seems to be related to a mechanically driven increase in osteocyte apoptosis [45,46,49].”
- Authors
- Smith, J. K.
- Affiliations
- East Tennessee State University (US)
- Corresponding author
- Smith, John Kelly
- ORCID
- Smith, John Kelly
- Venue
- Life
- Publisher
- MDPI AG
- Published
- 2020-09-16
- Volume
- 10
- Issue
- 9
- Pages
- 207
- ISSN
- 2075-1729 (ISSN-L)
- PMC
- PMC7555718
- OpenAlex
- W3046517779
- Semantic Scholar
- ec6857e1a562ff86cd8b6b428bdee49586bb8e38
- Cited by
- 52
- References
- 79
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 11 · 2023: 9 · 2022: 7 · 2021: 8 · 2020: 1
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Life (publishedVersion, cc-by)
- Preprints.org (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Physiology › Spaceflight effects on biology
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- osteoclasts, microgravity, osteoclastogenesis, hematopoietic stem cells, macrophage colony-stimulating factor, RANKL, calcineurin, bone formation, simulated microgravity, bone resorption
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
