Hormone-Receptor-MMP Axis in Degenerative TMJ Diseases

描述（由申请方提供）：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颞下颌关节（TMJ）纤维软骨退化的机制，这些机制可能导致TMJ疾病（TMJD）。TMJD的症状，如疼痛和下颌运动受限，在美国约有1000万人。由于这些疾病在育龄女性中非常普遍，因此人们认为女性性激素有助于这些疾病的发生或进展。在支持这一概念，我们已经证明，松弛素和/或雌激素的增加和孕激素减弱特定的基质金属蛋白酶（MMP）组织降解酶的表达，并改变TMJ盘纤维软骨的基质组成。然而，几个关键的问题，包括（1）松弛素，雌激素和孕激素的相对全身浓度对体内TMJ组织的净基质含量的影响的测定，以及（2）参与激素介导的关节退行性变的MMPs和激素受体的鉴定仍然没有答案。我们将通过验证松弛素和β-雌二醇通过激活特异性受体促进关键的胶原和蛋白聚糖降解MMP的表达，而孕酮减弱这种降解反应，从而有助于TMJ纤维软骨组织的靶向降解的假设来解决这些问题。具体而言，我们将（1）确定松弛素和孕酮在体内分别增强和减弱TMJ椎间盘基质损失的剂量反应效应，（2）使用特定MMP敲除小鼠来鉴定参与关节诱导组织降解的MMP酶，以及（3）使用特定雌激素和松弛素受体敲除小鼠来鉴定有助于关节组织变性的受体。该申请解决了计划公告的主要目标，即利用“转基因小鼠模型探索非炎性关节变性的生物学机制。“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性的治疗靶点，这对于预防或缓解这些疾病的进展至关重要。

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.