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Preventing Cartilage Degeneration in Warfighters by Elucidating Novel Mechanisms Regulating Osteocyte-Mediated Perilacunar Bone Remodeling

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University of California San Francisco San Francisco United States

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Our overall hypothesis is that an adverse biologic response to protracted high mechanical loads compromises osteocyte-mediated perilacunar remodeling PLR, bone quality, and cartilage health in post-traumatic osteoarthritis PTOA. Few molecular details are known about the regulation of PLR or bone quality in healthy bone or in disease. Therefore, we will test the hypothesis that mechanical load and TGFbeta signaling interact to regulate PLR, and that this regulation is impaired in, contributes to, and can be targeted for prevention of, the progression of PTOA. We are testing this hypothesis using mouse models and human PTOA tissue. We aim to determine 1 the extent to which mechanical loading regulates PLR in a TGFbeta-dependent manner, 2 the relationship among PLR, strain, TGFbeta, and cartilage degeneration, and 3 the causality of PLR in cartilage degeneration. During the first year, we have rigorously validated approaches, developed new protocols, and generated new reagents to address these questions. The first mouse and human specimens needed to test these hypotheses have been collected and are currently being analyzed. Preliminary analysis of gene expression supports the hypothesis that PLR is TGFbeta-regulated. Subsequent studies will use these approaches to answer the significant questions posed by this project. Since osteocytes have not been implicated in OA, understanding their role in disease has significant potential to yield new drug targets to impede cartilage degeneration.

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Technical Report,30 Sep 2014,29 Sep 2015



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Approved For Public Release;

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