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Microgravity Induces Pelvic Bone Loss through Osteoclastic Activity, Osteocytic Osteolysis, and Osteoblastic Cell Cycle Inhibition by CDKN1a/p21
Open accessAbstract
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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“They also documented osteocyte apoptosis as reflected by increases in lacunar and canalicular diameters [60].”
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“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.”
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“conditions of microgravity and simulated microgravity decrease the mineral content and cortical and trabecular microstructures of bone”
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“decrease osteoblastogenesis and osteoblast secretion of OPG”
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“increase osteoclast differentiation, fusion, and expression of regulatory and osteoclast-specific genes”
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“increase osteoclast secretion of sclerostin”
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Metadata
- 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.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-04-18
- Volume
- 8
- Issue
- 4
- Pages
- e61372
- ISSN
- 1932-6203 (ISSN-L)
- 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
- gold
- doi.org
- 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 (medical) › 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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