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Cited by 220Bone Metabolism and DiseasesBone health and osteoporosis researchEstrogen and related hormone effects

Osteocyte apoptosis and control of bone resorption following ovariectomy in mice

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Emerton, K.B., Hu, B., Woo, A.A., Sinofsky, A., Hernandez, C., Majeska, R.J., Jepsen, K.J., Schaffler, M.B.·2010·Bone
DOI 10.1016/j.bone.2009.11.006PMC PMC2824001
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Abstract

Introduction Osteocyte apoptosis has been linked to bone resorption resulting from estrogen depletion and other resorptive stimuli; however, precise spatial and temporal relationships between the two events have not been clearly established. The purpose of this study was to characterize the patterns of osteocyte apoptosis in relation to bone resorption following ovariectomy to test whether osteocyte apoptosis occurs preferentially in areas known to activate resorption. Moreover, we report that osteocyte apoptosis is necessary to initiate endocortical remodeling in response to estrogen withdrawal.Materials and methods Adult female C57BL/6J mice (17 weeks old) underwent either bilateral ovariectomy (OVX), or sham surgery (SHAM) and were euthanized on days 3, 7, 14, or 21 days after OVX. Diaphyseal cross-sections were stained by immunohistochemistry for activated caspase-3 as a marker of apoptosis. The percentages of caspase-positive stained osteocytes (Casp+Ot.) were measured along major and minor anatomical axes around the femoral diaphysis to evaluate the distribution of osteocyte apoptosis after estrogen loss; resorption surface was measured at the adjacent endocortical regions. In a second study to test whether osteocyte apoptosis plays a regulatory role in the initiation of bone resorption, a group of OVX mice received the pan-caspase inhibitor, QVDOPh, to inhibit osteocyte apoptosis. Remaining experimental and sham groups received either QVD or Vehicle.Results OVX increased osteocyte apoptosis in a non-uniform distribution throughout the femoral diaphyses. Increases in Casp+osteocytes were predominantly located in the posterior diaphyseal cortex. Here, the number of apoptotic osteocytes 4- to 7-fold higher than sham controls (p<0.005) by day 3 post-OVX and remained elevated. Increases in resorption post-OVX also occurred along the posterior endocortical surface overlying the region of osteocyte apoptosis, but these increases occurred only at 14 and 21 days post-OVX (p<0.002) well after the increases in osteocyte apoptosis. Treatment with QVD in OVX animals suppressed osteocyte apoptosis, with levels in QVD-treated samples equivalent to baseline. Moreover, the increases in osteoclastic resorption normally observed after estrogen loss did not occur in OVX mice treated with QVD.Conclusions The results of this study demonstrate that osteocyte apoptosis following estrogen loss occur regionally, rather than uniformly throughout the cortex. We also showed that estrogen loss increased osteocyte apoptosis. Apoptotic osteocytes were overwhelmingly localized within the posterior cortical region, the location where endocortical resorption was subsequently activated in ovariectomized mice. Finally, the increases in osteoclastic resorption normally observed after estrogen withdrawal did not occur in the absence of osteocyte apoptosis indicating that this apoptosis is necessary to activate endocortical remodeling following estrogen loss.

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  • Estrogen prevents excessive bone resorption.

    “Nevertheless, several studies have shown that estrogen maintains bone homeostasis by inhibiting osteoblast and osteocyte apoptosis [151–153] and preventing excessive bone resorption.”

    From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [153]

  • Estrogen maintains bone homeostasis by inhibiting osteoblast and osteocyte apoptosis.

    “Nevertheless, several studies have shown that estrogen maintains bone homeostasis by inhibiting osteoblast and osteocyte apoptosis [151–153] and preventing excessive bone resorption.”

    From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [153]

  • In vivo, osteocyte apoptosis is fundamental for initiating bone remodeling, independent of the stimulus causing osteocyte death such as estrogen loss, fatigue, or unloading.

    “In vivo, osteocyte apoptosis is fundamental for initiating bone remodeling,61 independent of the stimulus causing osteocyte death such as estrogen loss,62 fatigue,63 or unloading.64”

    From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [62]

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Authors
Emerton, K. B., Hu, B., Woo, A. A., Sinofsky, A., Hernandez, C., Majeska, R. J., Jepsen, K. J., & Schaffler, M. B.
Affiliations
  • City College of New York (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Case Western Reserve University (US)
ORCID
Venue
Bone
Publisher
Elsevier BV
Published
2010-03
Volume
46
Issue
3
Pages
577-583
ISSN
  • 1873-2763 (ISSN-L)
  • 8756-3282
DOI
10.1016/j.bone.2009.11.006
PMC
PMC2824001
OpenAlex
W1978413495
Cited by
220
References
66
Citations by year
2026: 6 · 2025: 11 · 2024: 10 · 2023: 12 · 2022: 14 · 2021: 19 · 2020: 19 · 2019: 13 · 2018: 17 · 2017: 6 · 2016: 13 · 2015: 12 · 2014: 16 · 2013: 11 · 2012: 19
FWCI
5.51
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Bone (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR41210, AR44927)
  • National Space Biomedical Research Institute
Topics
  • 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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
osteocyte apoptosis, bone resorption, ovariectomy, estrogen withdrawal, caspase-3, femoral diaphysis, osteoclasts, bone remodeling, estrogen deficiency, caspase inhibition, mice, bone loss, menopause model
MeSH terms
Animals, Bone Resorption, Female, Mice, Inbred C57BL, Osteocytes, Ovariectomy, Time Factors, Apoptosis, Mice

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