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Cited by 198Spaceflight effects on biologyBone Metabolism and DiseasesBone health and osteoporosis research

Microgravity Induces Pelvic Bone Loss through Osteoclastic Activity, Osteocytic Osteolysis, and Osteoblastic Cell Cycle Inhibition by CDKN1a/p21

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Blaber, Elizabeth A., Dvorochkin, Natalya, Lee, Chialing, Alwood, Joshua S., Yousuf, Rukhsana, Pianetta, Piero, Globus, Ruth K., Burns, Brendan P. +1 more·2013·PLoS ONE
DOI 10.1371/journal.pone.0061372PMC PMC3630201
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Abstract

Bone is a dynamically remodeled tissue that requires gravity-mediated mechanical stimulation for maintenance of mineral content and structure. Homeostasis in bone occurs through a balance in the activities and signaling of osteoclasts, osteoblasts, and osteocytes, as well as proliferation and differentiation of their stem cell progenitors. Microgravity and unloading are known to cause osteoclast-mediated bone resorption; however, we hypothesize that osteocytic osteolysis, and cell cycle arrest during osteogenesis may also contribute to bone loss in space. To test this possibility, we exposed 16-week-old female C57BL/6J mice (n = 8) to microgravity for 15-days on the STS-131 space shuttle mission. Analysis of the pelvis by µCT shows decreases in bone volume fraction (BV/TV) of 6.29%, and bone thickness of 11.91%. TRAP-positive osteoclast-covered trabecular bone surfaces also increased in microgravity by 170% (p = 0.004), indicating osteoclastic bone degeneration. High-resolution X-ray nanoCT studies revealed signs of lacunar osteolysis, including increases in cross-sectional area (+17%, p = 0.022), perimeter (+14%, p = 0.008), and canalicular diameter (+6%, p = 0.037). Expression of matrix metalloproteinases (MMP) 1, 3, and 10 in bone, as measured by RT-qPCR, was also up-regulated in microgravity (+12.94, +2.98 and +16.85 fold respectively, p<0.01), with MMP10 localized to osteocytes, and consistent with induction of osteocytic osteolysis. Furthermore, expression of CDKN1a/p21 in bone increased 3.31 fold (p<0.01), and was localized to osteoblasts, possibly inhibiting the cell cycle during tissue regeneration as well as conferring apoptosis resistance to these cells. Finally the apoptosis inducer Trp53 was down-regulated by -1.54 fold (p<0.01), possibly associated with the quiescent survival-promoting function of CDKN1a/p21. In conclusion, our findings identify the pelvic and femoral region of the mouse skeleton as an active site of rapid bone loss in microgravity, and indicate that this loss is not limited to osteoclastic degradation. Therefore, this study offers new evidence for microgravity-induced osteocytic osteolysis, and CDKN1a/p21-mediated osteogenic cell cycle arrest.

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  • 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].”

    From Osteoclasts and Microgravity (2020) · cites this paper as [60]

    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)

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  • In 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.”

    From Osteoclasts and Microgravity (2020) · cites this paper as [60]

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  • Conditions 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”

    From Osteoclasts and Microgravity (2020) · cites this paper as [60]

    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)

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  • 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 [60]

    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)

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  • 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 [60]

    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)

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Authors
Blaber, E. A., Dvorochkin, N., Lee, C., Alwood, J. S., Yousuf, R., Pianetta, P., Globus, R. K., Burns, B. P., & Almeida, E. A. C.
Affiliations
  • Ames Research Center (US)
  • SLAC National Accelerator Laboratory (US)
  • UNSW Sydney (AU)
Corresponding author
Almeida, Eduardo A. C.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-04-18
Volume
8
Issue
4
Pages
e61372
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0061372
PMC
PMC3630201
OpenAlex
W2142491318
Cited by
196
References
74
Citations by year
2026: 15 · 2025: 17 · 2024: 10 · 2023: 9 · 2022: 9 · 2021: 21 · 2020: 21 · 2019: 16 · 2018: 19 · 2017: 11 · 2016: 15 · 2015: 12 · 2014: 19 · 2013: 2
FWCI
11.14
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Aeronautics and Space Administration
Topics
  • Health Sciences › Medicine › Physiology › Spaceflight effects on biology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords
microgravity, spaceflight, bone loss, osteoclasts, osteoblasts, CDKN1A/p21, Trp53, matrix metalloproteinases, osteocytes, bone resorption, trabecular bone, bone unloading, female mice, bone homeostasis
MeSH terms
Animals, Bone and Bones, Bone Resorption, Female, Mice, Inbred C57BL, Osteoclasts, Osteocytes, Osteolysis, Pelvic Bones, Weightlessness, Cyclin-Dependent Kinase Inhibitor p21, Mice, X-Ray Microtomography, Cell Cycle Checkpoints

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