Hormone-Receptor-MMP Axis in Degenerative TMJ Diseases

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DESCRIPTION (provided by applicant): The overall purpose of these studies is to dissect the mechanisms by which female reproductive hormones, relaxin, estrogen, and progesterone, and their receptors contribute to the degeneration of temporomandibular joint (TMJ) fibrocartilage potentially contributing to TMJ disorders (TMJDs). The symptoms of TMJDs such as pain and limited jaw movement occur in approximately 10 million individuals in the USA. Since these disorders are highly prevalent in women of reproductive age, it has been posited that female sex hormones contribute to the initiation or progression of these disorders. In support of this concept, we have demonstrated that relaxin and / or estrogen increase and progesterone attenuates the expression of specific matrix metalloproteinase (MMP) tissue degrading enzymes and alter the matrix composition of the TMJ disc fibrocartilage. Nevertheless, several critical questions including (1) the determination of the effects of relative systemic concentrations of relaxin, estrogen and progesterone on net matrix content of TMJ tissues in vivo, and (2) the identification of MMPs and hormone receptors involved in hormone mediated joint degeneration remain unanswered. We will address these questions by testing the hypothesis that relaxin and (3-estradiol contribute to the targeted degradation of fibrocartilaginous tissues of the TMJ by activation of specific receptors to enhance the expression of key collagen- and proteoglycan-degrading MMPs, while progesterone attenuates this degradative response. Specifically, we will (1) determine the dose response effects of relaxin and progesterone in respectively enhancing and attenuating TMJ disc matrix loss in vivo, (2) use specific MMP knockout mice to identify the MMP enzymes involved in hormonally induced tissue degradation, and (3) utilize specific estrogen and relaxin receptor knockout mice to identify the receptors that contribute to joint tissue degeneration. This application addresses the primary objective of the Program Announcement namely to utilize "genetically modified mouse models to explore the biological mechanisms underlying non-inflammatory joint degeneration." Identification of the MMPs and receptors involved in hormone mediated degradation of TMJ fibrocartilage will provide early and specific therapeutic targets during reversible stages of the disease process that would be important in preventing or alleviating the progression of these disorders.