Altered post-fracture systemic bone loss in a mouse model of osteocyte dysfunction

Osipov, Benjamin; Emami, Armaun J.; Cunningham, Hailey C.; Orr, Sophie; Lin, Yu-Yang; Jbeily, Elias H.; Punati, Ritvik S.; Murugesh, Deepa K.; Zukowski, Hannah M.; Loots, Gabriela G.; Carney, Randy; Vargas, Diego; Ferguson, Virginia L.; Christiansen, Blaine A.

doi:10.1093/jbmrpl/ziae135

Altered post-fracture systemic bone loss in a mouse model of osteocyte dysfunction

Journal Article · Fri Nov 01 00:00:00 EDT 2024 · JBMR Plus

DOI:https://doi.org/10.1093/jbmrpl/ziae135· OSTI ID:2499586

^[1]; Emami, Armaun J. ^[1]; Cunningham, Hailey C. ^[1]; Orr, Sophie ^[1]; Lin, Yu-Yang ^[1]; Jbeily, Elias H. ^[1]; Punati, Ritvik S. ^[1]; Murugesh, Deepa K. ^[2]; Zukowski, Hannah M. ^[1]; ^[3]; Carney, Randy ^[4]; Vargas, Diego ^[5]; Ferguson, Virginia L. ^[5]; ^[1]

Univ. of California Davis Medical Center, Sacramento, CA (United States)
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Univ. of California Davis Medical Center, Sacramento, CA (United States); Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Univ. of California, Davis, CA (United States)
Univ. of Colorado, Boulder, CO (United States)

Femur fracture leads to loss of bone at uninjured skeletal sites, which may increase risk of subsequent fracture. Osteocytes, the most abundant bone cells, can directly resorb bone matrix and regulate osteoclast and osteoblast activity, but their role in systemic bone loss after fracture remains poorly understood. In this study we used a transgenic (TG+) mouse model that overexpresses human B-cell lymphoma 2 (BCL-2) in osteoblasts and osteocytes. This causes enhanced osteoblast proliferation, followed by disruption in lacunar-canalicular connectivity and massive osteocyte death by 10 wk of age. We hypothesized that reduced viable osteocyte density would decrease the magnitude of systemic bone loss after femur fracture, reduce perilacunar remodeling, and alter callus formation. Bone remodeling was assessed using serum biomarkers of bone formation and resorption at 5 d post-fracture. We used micro-computed tomography, high resolution x-ray microscopy, mechanical testing, and Raman spectroscopy to quantify the magnitude of systemic bone loss, as well as changes in osteocyte lacunar volume, bone strength, and bone composition 2 wk post-fracture. Fracture was associated with a reduction in circulating markers of bone resorption in non-transgenic (TG-) animals. TG+ mice exhibited high bone mass in the limbs, greater cortical elastic modulus and reduced post-yield displacement. After fracture, TG+ mice lost less trabecular bone than TG- mice, but conversely TG+ mice exhibited trends toward a lower yield point and reduced femoral cortical thickness after fracture, though these were not statistically significant. Lacunar density was greater in TG+ mice, but fracture did not alter lacunar volume in TG+ or TG- mice. These findings suggest that osteocytes potentially play a significant role in the post-traumatic systemic response to fracture, though the effects differ between trabecular and cortical bone.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 2499586

Report Number(s):: LLNL--JRNL-2001934

Journal Information:: JBMR Plus, Journal Name: JBMR Plus Journal Issue: 12 Vol. 8; ISSN 2473-4039

Publisher:: Wiley - American Society for Bone and Mineral ResearchCopyright Statement

Country of Publication:: United States

Language:: English

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