Hormone-Receptor-MMP Axis in Degenerative TMJ Diseases

描述（由申请人提供）：这些研究的总体目的是剖析女性生殖激素、松弛素、雌激素和孕激素及其受体对颞下颌关节（TMJ）纤维软骨退行性变的机制，这些退行性变可能导致TMJ疾病（TMJDs）。在美国，大约有1000万人患有TMJDs的症状，如疼痛和下颌运动受限。由于这些疾病在育龄妇女中非常普遍，因此有人认为女性性激素有助于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弱特定基质金属蛋白酶（MMP）组织降解酶的表达，并改变TMJ椎间盘纤维软骨的基质组成。然而，几个关键问题，包括(1)松弛素、雌激素和孕酮的相对全身浓度对体内TMJ组织净基质含量的影响的确定，以及(2)MMPs和激素受体参与激素介导的关节退行性变的鉴定仍然没有答案。我们将通过验证松弛素和（3-雌二醇）通过激活特定受体来促进TMJ纤维软骨组织的靶向降解来解决这些问题，从而增强关键的胶原和蛋白聚糖降解MMPs的表达，而黄体酮则减弱这种降解反应。具体而言，我们将(1)确定松弛素和黄体酮在体内分别增强和减弱TMJ椎间盘基质损失的剂量效应，(2)使用特异性MMP敲除小鼠鉴定激素诱导的组织降解中涉及的MMP酶，(3)使用特异性雌激素和松弛素受体敲除小鼠鉴定导致关节组织变性的受体。该申请解决了项目公告的主要目标，即利用“转基因小鼠模型探索非炎症性关节变性的生物学机制”。识别的基质金属蛋白酶和受体参与激素介导的颞下颌关节纤维软骨退化将提供早期和可逆阶段的疾病过程中具体的治疗目标,将重要的预防或减轻这些疾病的进展。

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.