Loss of Osteocyte Integrity in Association with Microdamage and Bone Remodeling After Fatigue In Vivo

Verborgt, Olivier; Gibson, Gary J.; Schaffler, Mitchell B.

doi:10.1359/jbmr.2000.15.1.60

Cited by 731Bone Metabolism and DiseasesBone health and osteoporosis researchSpaceflight effects on biology

Loss of Osteocyte Integrity in Association with Microdamage and Bone Remodeling After Fatigue In Vivo

Verborgt, Olivier, Gibson, Gary J., Schaffler, Mitchell B.·2000·Journal of Bone and Mineral Research

DOI 10.1359/jbmr.2000.15.1.60

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Abstract

As a result of fatigue, bone sustains microdamage, which is then repaired by bone-remodeling processes. How osteoclastic activity is targeted at the removal of microdamaged regions of bone matrix is unknown. In the current studies, we tested the hypothesis that changes in osteocyte integrity, through the initiation of regulated cell death (apoptosis), are associated with fatigue-related microdamage and bone resorption. Ulnae of adult rats were fatigue-loaded to produce a known degree of matrix damage. Osteocyte integrity was then assessed histomorphometrically from terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–nick end labeling (TUNEL)–stained sections to detect cells undergoing DNA fragmentation associated with apoptosis; toluidine blue–stained sections were used for secondary morphological confirmation. Ten days after loading, large numbers of TUNEL-positive osteocytes were found in bone surrounding microcracks and in bone surrounding intracortical resorption spaces (∼300% increases over controls, p < 0.005). TUNEL labeling in loaded ulnae at sites distant from microcracks or resorption foci did not differ from that in control bone. Osteocytes in toluidine blue–stained sections showed equivalent trends to TUNEL-stained sections, with significant increases in pyknotic nuclei and empty lacunae associated with microcracks and intracortical resorption spaces. TUNEL-positive osteocytes were observed around bone microdamage by 1 day after loading (p < 0.01 relative to baseline), and their number remained elevated throughout the entire experimental period. Increases in empty lacunae and decreases in normal osteocyte numbers were observed over time as well. These studies show that (1) osteocyte apoptosis is induced by bone fatigue, (2) this apoptosis is localized to regions of bone that contain microcracks, and (3) osteoclastic resorption after fatigue also coincides with regions of osteocyte apoptosis. The strong associations between microdamage, osteocyte apoptosis, and subsequent bone remodeling support the hypothesis that osteocyte apoptosis provides a key part of the activation or signaling mechanisms by which osteoclasts target bone for removal after fatigue-induced matrix injury.

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Osteocyte apoptosis acts as a chemotactic signal for local osteoclast recruitment.
“Osteocyte apoptosis has been shown to act as a chemotactic signal for local osteoclast recruitment [70, 150, 152, 190, 191].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [190]
In vivo anatomical studies have suggested that the presence of apoptotic osteocytes at microdamaged sites correlates with the recruitment of osteoclasts at microcracks.
“In vivo anatomical studies have suggested that the presence of apoptotic osteocytes at microdamaged sites correlates with the recruitment of osteoclasts at microcracks.48”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [48]

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Osteocyte Apoptosis Controls Activation of Intracortical Resorption in Response to Bone Fatigue
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Activation of bone remodeling after fatigue: Differential response to linear microcracks and diffuse damage
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Increased intracortical remodeling following fatigue damage
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Response of the osteocyte syncytium adjacent to and distant from linear microcracks during adaptation to cyclic fatigue loading
Colopy, S. A., Benz-Dean, J., Barrett, J. G., Sample, S. J., Lu, Y., Danova, N. A., Kalscheur, V. L., Vanderby, R., Markel, M. D., & Muir, P. (2004) · Bone · doi:10.1016/j.bone.2004.05.024 · Cited by 90 · see citing works

Authors: Verborgt, O., Gibson, G. J., & Schaffler, M. B.
Affiliations: University of Antwerp (BE)
Henry Ford Health (US)
Icahn School of Medicine at Mount Sinai (US)
Corresponding author: Schaffler, Mitchell B.
ORCID: Verborgt, Olivier
Schaffler, Mitchell B.
Venue: Journal of Bone and Mineral Research
Publisher: Oxford University Press (OUP)
Published: 2000-01-01
Volume: 15
Issue: 1
Pages: 60-67
ISSN: 0884-0431 (ISSN-L)
1523-4681
DOI: 10.1359/jbmr.2000.15.1.60
OpenAlex: W2020238012
Cited by: 731
References: 52
Citations by year: 2026: 10 · 2025: 18 · 2024: 9 · 2023: 23 · 2022: 23 · 2021: 21 · 2020: 29 · 2019: 38 · 2018: 31 · 2017: 28 · 2016: 31 · 2015: 39 · 2014: 30 · 2013: 40 · 2012: 32
FWCI: 10.13
Type: journal article
Language: en
Open access: closed
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: National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR044712, AR41210, R01AR041210, AR 44712)
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
Health Sciences › Medicine › Physiology › Spaceflight effects on biology
Keywords: osteocyte apoptosis, bone fatigue, microcracks, bone microdamage, bone remodeling, osteoclast resorption, ulna
MeSH terms: Animals, Female, Osteocytes, Stress, Physiological, Ulna, Bone Remodeling, Rats, Sprague-Dawley, In Situ Nick-End Labeling, Rats

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Loss of Osteocyte Integrity in Association with Microdamage and Bone Remodeling After Fatigue In Vivo

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