Bone fragility and joint disease present major challenges to the skeletal and dental health of the aging population. However, both conditions face a serious treatment gap. For example, therapies for bone fragility treat low bone mass, but overlook approximately 50% of fractures that result from impaired bone quality. Therapies to prevent or reverse joint degeneration remain elusive. The long-term goal of this research is to overcome this treatment gap by elucidating the cellular and molecular mechanisms that maintain bone quality and joint homeostasis. Ongoing efforts highlight the critical role of osteocytes in both processes, as well as their contribution to bone fragility and joint disease. Osteocytes play a fundamental role in skeletal homeostasis and disease through the process of perilacunar canalicular remodeling (PLR). In PLR, osteocytes secrete acid and proteases to dynamically resorb, and then replace, the surrounding bone matrix. PLR maintains the canalicular network and bone matrix material properties, a major aspect of bone quality. Indeed, osteocyte-intrinsic disruption of TGF? signaling in T?RIIocy-/- mice results in a 65% decline in femoral work to fracture, even with normal cortical bone mass. Preliminary and newly published data document profound PLR suppression in human osteoarthritis, and provide evidence that PLR defects play a causal role in joint degeneration in both T?RIIocy-/- mice and in mice with osteocyte-intrinsic ablation of the PLR enzyme MMP13 (MMP13ocy-/-). Furthermore, PLR is suppressed in aging bone in much the same manner as in both mouse models. Although these findings suggest a role for TGF?, MMP13, and PLR in the age-related decline in bone quality and joint health, the mechanisms responsible for PLR suppression in aging, or by which PLR suppression contributes to skeletal disease are mostly unknown. RNAseq of T?RIIocy-/-, MMP13ocy-/-, and aging bone reveals evidence of mitochondrial dysfunction in each model, a possibility that will be further explored in this project. A computational approach will be used to integrate genome-wide mouse RNAseq and human GWAS data to improve the identification of novel, clinically-relevant genes involved in bone fragility and osteoarthritis. These results will prioritize mechanistic gain and loss of function studies to test the hypothesis that TGF?-dependent PLR suppression and osteocyte mitochondrial dysfunction play a causal role in the age-related decline in bone quality and joint health. The proposal pursues three specific aims: 1) to determine the role of TGF? and PLR in age-dependent loss of bone quality and joint homeostasis, 2) to identify PLR-dependent mechanisms implicated in human bone fragility and joint disease, and 3) to identify mechanisms by which PLR and mitochondrial function are deregulated in aging. These studies will reveal if PLR suppression in aging represents a common cellular mechanism that drives the temporal decline of bone quality and joint health, and further, if the unique metabolic control of osteocytes creates opportunities to specifically target this cell population to improve skeletal and dental health in aging.
The active role of osteocytes, cells embedded within bone, in maintaining skeletal health is disrupted with aging. Here we test the possibility that the disruption of osteocyte function with age contributes to age-related bone fragility and joint degeneration. Testing this hypothesis will advance our understanding of the cellular and molecular mechanisms controlling bone quality and joint disease, which will improve the success of clinical efforts to protect musculoskeletal health throughout the lifespan.
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