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Cited by 80Bone Metabolism and DiseasesSpaceflight effects on biologyBone health and osteoporosis research

Modeled microgravity and hindlimb unloading sensitize osteoclast precursors to RANKL-mediated osteoclastogenesis

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Saxena, Ritu, Pan, George, Dohm, Erik D., McDonald, Jay M.·2011·Journal of Bone and Mineral Metabolism
DOI 10.1007/s00774-010-0201-4PMC PMC3000895
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Abstract

Mechanical forces are essential to maintain skeletal integrity, and microgravity exposure leads to bone loss. The underlying molecular mechanisms leading to the changes in osteoblasts and osteoclast differentiation and function remain to be fully elucidated. Because of the infrequency of spaceflights and payload constraints, establishing in vitro and in vivo systems that mimic microgravity conditions becomes necessary. We have established a simulated microgravity (modeled microgravity, MMG) system to study the changes induced in osteoclast precursors. We observed that MMG, on its own, was unable to induce osteoclastogenesis of osteoclast precursors; however, 24 h of MMG activates osteoclastogenesis-related signaling molecules ERK, p38, PLCγ2, and NFATc1. Receptor activator of NFkB ligand (RANKL) (with or without M-CSF) stimulation for 3-4 days in gravity of cells that had been exposed to MMG for 24 h enhanced the formation of very large tartrate-resistant acid phosphatase (TRAP)-positive multinucleated (>30 nuclei) osteoclasts accompanied by an upregulation of the osteoclast marker genes TRAP and cathepsin K. To validate the in vitro system, we studied the hindlimb unloading (HLU) system using BALB/c mice and observed a decrease in BMD of femurs and a loss of 3D microstructure of both cortical and trabecular bone as determined by micro-CT. There was a marked stimulation of osteoclastogenesis as determined by the total number of TRAP-positive multinucleated osteoclasts formed and also an increase in RANKL-stimulated osteoclastogenesis from precursors removed from the tibias of mice after 28 days of HLU. In contrast to earlier reported findings, we did not observe any histomorphometric changes in the bone formation parameters. Thus, the foregoing observations indicate that microgravity sensitizes osteoclast precursors for increased differentiation. The in vitro model system described here is potentially a valid system for testing drugs for preventing microgravity-induced bone loss by targeting the molecular events occurring in microgravity-induced enhanced osteoclastogenesis.

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  • Conditions of microgravity and simulated microgravity increase osteoclast secretion of sclerostin.

    “increase osteoclast secretion of sclerostin”

    From Osteoclasts and Microgravity (2020) · cites this paper as [63]

    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.

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  • In 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.”

    From Osteoclasts and Microgravity (2020) · cites this paper as [63]

    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

  • Conditions of microgravity and simulated microgravity decrease osteoblastogenesis and osteoblast secretion of OPG.

    “decrease osteoblastogenesis and osteoblast secretion of OPG”

    From Osteoclasts and Microgravity (2020) · cites this paper as [63]

    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

  • Modeled 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].”

    From Osteoclasts and Microgravity (2020) · cites this paper as [63]

    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

  • Conditions 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”

    From Osteoclasts and Microgravity (2020) · cites this paper as [63]

    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

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Authors
Saxena, R., Pan, G., Dohm, E. D., & McDonald, J. M.
Affiliations
  • Peoria campus of the University of Illinois System (US)
  • Emory University (US)
  • University of Alabama at Birmingham (US)
  • United States Department of Veterans Affairs (US)
Corresponding author
McDonald, Jay M.
ORCID
Dohm, Erik D.
Venue
Journal of Bone and Mineral Metabolism
Publisher
Springer Science and Business Media LLC
Published
2010-06-30
Volume
29
Issue
1
Pages
111-122
ISSN
  • 0914-8779 (ISSN-L)
  • 1435-5604
DOI
10.1007/s00774-010-0201-4
PMC
PMC3000895
OpenAlex
W2093433426
Cited by
80
References
1
Citations by year
2026: 4 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 7 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 4 · 2014: 9 · 2013: 4 · 2012: 4
FWCI
1.83
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Journal of Bone and Mineral Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Aeronautics and Space Administration
  • National Institutes of Health
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR046031, R01AR050235)
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
hindlimb unloading, osteoclastogenesis, osteoclast precursors, RANKL, mechanotransduction, ERK signaling, p38 MAPK, PLCγ2, NFATc1, cathepsin K, bone mineral density, bone microarchitecture, macrophage colony-stimulating factor
MeSH terms
Tartrate-Resistant Acid Phosphatase, Acid Phosphatase, Animals, Cell Line, Isoenzymes, Male, Mice, Inbred BALB C, Osteoblasts, Osteoclasts, Weightlessness, Blotting, Western, Bone Density, Apoptosis, Hindlimb Suspension, Reverse Transcriptase Polymerase Chain Reaction, Mice, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B

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