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

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

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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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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
Published
2013-04-18
Volume
8
Issue
4
Pages
e61372
ISSN
1932-6203 (ISSN-L)
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
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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