Age-related bone loss puts individuals at risk for debilitating fractures that increase the risk for morbidity and mortality. Osteocytes make up 95% of the skeleton and are increasingly recognized as master regulators of bone homeostasis. With age there is reduced osteocyte density, and selective deletion of osteocytes results in osteoporosis. This suggests that maintaining osteocyte viability and function may be an effective strategy to mitigate age-related bone loss. Osteocytes are well-known to regulate osteoclasts; however, the potential effects of osteoclasts on osteocytes have not been evaluated. Preliminary data suggest that mice with impaired osteoclast TGF-? signaling exhibit increased osteocyte apoptosis in vivo, and TGF-? treated osteoclast conditioned media protects osteocytes from dexamethasone-induced apoptosis in vitro. A role for osteoclasts in promoting osteocyte viability and/or function, a relationship supported by my preliminary data, would have important implications for the majority of osteoporosis therapies that act by reducing osteoclast numbers. The overall goal of this five year career development application is to test the hypothesis that TGF-? signaling in osteoclasts induces the production of paracrine factors that promote osteocyte viability necessary to maintain skeletal homeostasis. Specifically, I will complete the characterization of the osteocyte phenotype in mice with impaired osteoclast TGF-? signaling and evaluate the mechanism by which TGF-? signaling in osteoclasts promotes osteocyte viability in vitro and in vivo. Secondly, I will evaluate the effect of osteoclast ablation/depletion on osteocytes in mice and humans through genetic (mouse) and pharmacologic (humans) methods. This proposal offers significant training opportunities in osteocyte phenotyping techniques, including acid etching/scanning electron microscopy, analysis of the functional response of osteocytes to in vivo axial loading, as well as direct analysis of osteocyte gene expression without in vitro culture. In addition, studying the effects of pharmacological depletion of osteoclasts on osteocytes in humans offers valuable experience in clinical mechanistic research. Correlating the results of animal studies to humans is crucial to advancing basic findings to the clinic. Therefore, the proposed studies will provide me with training essential to my career development and lay the ground work for developing an independent R01 application.
Osteoporosis affects approximately 10 million Americans, while another 34 million are suspected to have low bone mass putting them at risk for developing the disease. In 2005 the U.S. was estimated to have spent $17 billion on costs related to osteoporotic fractures; these costs are expected to rise to greater than $25 billion by 2025 with the increasing aging population. The majority of current osteoporosis therapies reduce the number of bone resorbing osteoclasts, and as a result, indirectly reduce new bone formation; therefore, an understanding of the role of osteoclasts in promoting bone homeostasis is critical to the development of osteoporosis therapies that reduce bone loss while preserving bone formation.
|Xu, Ming; Pirtskhalava, Tamar; Farr, Joshua N et al. (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246-1256|
|Farr, Joshua N; Weivoda, Megan M; Nicks, Kristy M et al. (2018) Osteoprotection Through the Deletion of the Transcription Factor Ror? in Mice. J Bone Miner Res 33:720-731|
|Farr, Joshua N; Xu, Ming; Weivoda, Megan M et al. (2017) Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 23:1072-1079|
|Weivoda, Megan M; Youssef, Stephanie J; Oursler, Merry Jo (2017) Sclerostin expression and functions beyond the osteocyte. Bone 96:45-50|