The role of FGFR3 in the effects of PTH in the Mandibular Condyle

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Abstract Career Development: This K01 application describes a 5-year training program to support my career development as an independent clinician-scientist. My goal is to expand my research experience to achieve my long-term goal of directing a translational research program in temporomandibular joint osteoarthritis (TMJ-OA) regeneration. This K01 award will provide me with the guidance and protected time necessary to achieve the following goals: (1) To complete the studies outlined in Specific Aims 1 and 2. (2) To translate the basic research findings into clinical applications that can benefit patients with painful and disabling degenerative TMD disorders. (3) To be actively involved in mentoring the next generation of clinician/scientists, promoting the inclusion of underrepresented individuals into health professions and craniofacial research. To achieve the listed goals, I have assembled a multidisciplinary mentoring team of experts in craniofacial translational research, musculoskeletal health as well as academic leadership in diversity promotion in the School of Dental Medicine. Science: TMJ-OA is a degenerative joint disease characterized by cartilage loss and sclerosis of the subchondral bone, causing pain and disability. There is an unmet clinical need to develop therapeutic interventions that are anabolic for the TMJ which could prevent or reverse degeneration of the TMJ cartilage. We have identified that the FDA approved treatment, intermittent parathyroid hormone (I-PTH), promotes anabolic responses in the osteochondral tissues of the TMJ. Our goal is to gain insights into the cellular and molecular mechanisms by which these effects are exerted. Our central hypothesis is that FGFR3 is the master regulator of the anabolic response observed in the TMJ due to I-PTH administration. This hypothesis will be tested by following specific aims: Specific Aim 1A: To determine the role of FGFR3 signaling in the anabolic effects of I-PTH administration in the MCC of the TMJ. We will delete FGFR3 in αSMA expressing cells in the mandibular condylar cartilage (MCC) and determine the effects of FGFR3 loss-of-function with and without I- PTH. We will also inject a soluble FGFR3 to rescue the FGFR3 conditional deleted to confirm that this signaling is the master regulator of the effects of I-PTH. Aim 1B: To define the molecular mechanism by which FGFR3 regulates the anabolic effects of I-PTH in vitro. FGFR3 in the primary chondrocytes from the MCC of triple collagen transgenic reporter mice will be inhibited using RNA silencing and specific FGFR3 inhibitor. Specific Aim 2: Evaluate the role Intermittent PTH plays in a model of cartilage injury and repair. The MCC of triple transgenic reporter mice will be injured and animals will receive either injected with I-PTH or saline to understand the role of I-PTH in early and delayed healing of the MCC.