Spatial Distribution of Bax and Bcl-2 in Osteocytes After Bone Fatigue: Complementary Roles in Bone Remodeling Regulation?
Open accessAbstract
Osteocyte apoptosis appears to play a key role in the mechanism by which osteoclastic resorption activity targets bone for removal, because osteocyte apoptosis occurs in highly specific association with microdamage and subsequent remodeling after fatigue. However, beyond terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) assay, little is known about the mechanisms controlling osteocyte apoptosis in vivo. In the current studies, expression of Bax, a proapoptotic gene product, and Bcl-2, an antiapoptotic gene product, was determined in osteocytes of fatigued rat bone using immunocytochemical staining and compared with TUNEL staining patterns. Bax and Bcl-2 were evident in osteocytes by 6 h after loading. Moreover, Bax and Bcl-2 in osteocytes were expressed differently as a function of distance from microdamage sites. The peak of Bax expression and TUNEL+ staining in osteocytes was observed immediately at the microcrack locus, which is where bone resorption occurs in this system; in contrast, Bcl-2 expression, the antiapoptotic signal, reached its greatest level at some distance (1-2 mm) from microcracks. These data suggest that near sites of microinjury in bone, those osteocytes that do not undergo apoptosis are prevented from doing so by active protection mechanisms. Moreover, the zone of apoptotic osteocytes around microcracks was effectively “walled in” by a surrounding halo of surviving osteocytes actively expressing Bcl-2. Thus, the expression pattern of apoptosis-inhibiting gene products by osteocytes surrounding the apoptotic osteocyte at microdamage sites also may provide important signals in the guidance of resorption processes that occur in association with osteocyte apoptosis after fatigue.
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Bystander osteocytes (in 1-2-mm proximity to the focal damage site) expressed the antiapoptotic protein BcL-2; this defense mechanism might be necessary to prevent osteoclastogenic signal damaging viable osteocytes.
“Moreover, bystander osteocytes (in 1–2-mm proximity to the focal damage site) expressed the antiapoptotic protein BcL-2. This defense mechanism might be necessary to prevent osteoclastogenic signal damaging viable osteocytes70 (Fig. 2).”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [70]
A variant of RANKL with changes in the RANK binding site still activates LGR4 signaling and inhibits osteoclastogenesis; it acts as an immunogen triggering anti-RANKL antibodies and might reduce risks linked to abrupt suspension of denosumab.
“This variant still activates LGR4 signaling and inhibits osteoclastogenesis. Moreover, it has been observed that this variant acts as an immunogen triggering the production of anti‐RANKL antibodies, and its use might reduce the risks linked to the abrupt suspension of denosumab use.173,70”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [70]
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Self-citation
- Authors
- Verborgt, O., Tatton, N. A., Majeska, R. J., & Schaffler, M. B.
- Affiliations
- University of Antwerp (BE)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Schaffler, Mitchell B.
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-05-01
- Volume
- 17
- Issue
- 5
- Pages
- 907-914
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W2029546905
- Cited by
- 192
- References
- 54
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 8 · 2023: 7 · 2022: 4 · 2021: 5 · 2020: 10 · 2019: 5 · 2018: 7 · 2017: 10 · 2016: 12 · 2015: 9 · 2014: 8 · 2013: 15 · 2012: 16
- FWCI
- 1.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- Universiteit Antwerpen
- National Institutes of Health (AR41210)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR41210, R01AR041210)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- osteocyte apoptosis, Bax, Bcl-2, bone fatigue, microcracks, bone microdamage, bone remodeling, osteoclast resorption, apoptosis regulation, rat bone
- MeSH terms
- Animals, Bone and Bones, Female, Immunohistochemistry, Osteocytes, Proto-Oncogene Proteins, Stress, Mechanical, Bone Remodeling, Rats, Sprague-Dawley, Apoptosis, Proto-Oncogene Proteins c-bcl-2, bcl-2-Associated X Protein, Rats
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