Hormone-Receptor-MMP Axis in Degenerative TMJ Diseases

描述(申请人提供)：这些研究的总体目的是剖析女性生殖激素、松弛素、雌激素和孕酮及其受体导致可能导致TMJ紊乱(TMJDS)的TMJ纤维软骨退化的机制。在美国，大约有1000万人出现TMJDS的症状，如疼痛和下巴活动受限。由于这些疾病在育龄妇女中非常普遍，所以一直认为女性性激素参与了这些疾病的开始或进展。为了支持这一概念，我们已经证明松弛素和/或雌激素增加和黄体酮减少了特定的基质金属蛋白酶组织降解酶的表达，并改变了TMJ间盘纤维软骨的基质成分。然而，(1)松弛素、雌激素和孕酮的相对系统浓度对体内TMJ组织净基质含量的影响，以及(2)参与激素介导的关节退变的MMPs和激素受体的鉴定等关键问题仍未得到回答。我们将通过检验以下假设来解决这些问题：松弛素和(3-雌二醇)通过激活特定的受体来增强关键的胶原和蛋白多糖降解MMPs的表达，而黄体酮则减弱这种降解反应，从而促进TMJ纤维软骨组织的靶向降解。具体地说，我们将(1)确定松弛素和孕酮在体内分别增强和减轻TMJ间盘基质丢失的剂量反应效应；(2)使用特定的基质金属蛋白酶基因敲除小鼠来鉴定与激素诱导的组织降解有关的基质金属蛋白酶；(3)利用特定的雌激素和松弛素受体基因敲除小鼠来识别导致关节组织退化的受体。该应用程序解决了该计划公告的主要目标，即利用“转基因小鼠模型来探索非炎症性关节退行性变的生物学机制。”识别参与激素介导的TMJ纤维软骨降解的MMPs和受体将在疾病过程的可逆阶段提供早期和特异的治疗靶点，这对于预防或缓解这些疾病的进展将是重要的。

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.