Mechanism of MMP gene induction in osteoarthritis

描述（由申请人提供）： 提出的研究目标是阐明基质的诱导机制 金属蛋白酶（MMP）在骨关节炎影响的软骨细胞 关节组织骨关节炎（OA）是由软骨退化的表现 导致关节骨之间的缓冲层完全丧失， 僵硬、肿胀和关节活动受限。在正常软骨中， 每种MMP的表达受到严格调控。然而，在OA条件下， 过度表达导致胶原蛋白和其他关节 组织相关蛋白，维持正常环境所必需的， 软骨我们假设，一组转录因子，负责 MMPs的表达增加，存在于一个更高的活性水平， OA-软骨的软骨细胞。根据这一假设，初步 研究表明，OA关节组织的软骨细胞含有 几种转录因子的水平显著较高，其中一种是 被鉴定为SAF-1，一种炎症反应性转录因子。 SAF-1过表达对软骨细胞MMP-1表达的影响 细胞SAF-1还与MMP-9和-14基因的启动子相互作用 提示其可能在调节OA中这些MMP基因的表达中起作用 条件对相关转录因子的鉴定将提供一个 为将来的治疗努力调节其活性的分子基础 对抗OA因此，本研究的重点是确定SAF-1在以下方面的作用： 调节MMP-1、MMP-9和MMP-14基因的表达。这项提案的另一个目标是 是鉴定参与这一过程的其他转录因子。虽然 OA的病理学很可能始于软骨上的生物力学应力， 细胞因子出现在疾病的后期。因此，一个类似OA的 将通过结合生物力学应力和细胞因子来创建条件 MMP基因的诱导机制将在这些反应中进行研究 信号.为实现这一目标，计划实现以下具体目标： 在软骨细胞中鉴定SAF-1在MMP-1基因诱导中的作用， OA软骨确定涉及的其他响应要素和因素 增加OA条件下MMP-1的表达。2)调查SAF-1的作用 在OA-软骨中诱导MMP-9基因表达。识别其他 这一过程中涉及的调控因素。3)评估的作用 SAF-1诱导MMP-1 4基因表达并鉴定其他调控元件 以及参与增加软骨细胞中MMP-1 4表达的因素。 OA样症状 上述实验目标的完成将为今后的研究奠定基础。 研究：a）OA软骨细胞中的跨膜信号传导途径， 增强转录活性，和B）评估所涉及的 信号通路作为控制异常MMP的潜在治疗剂 表情

DESCRIPTION (provided by applicant): The goal proposed research is to elucidate the induction mechanism of matrix metalloproteinases (MMP) in chondrocyte cells of the osteoarthritis-affected joint tissue. Osteoarthritis (OA) is manifested by the degradation of cartilage leading to a total loss of the cushion between the bones of the joints causing stiffness, swelling and limitation of joint mobility. In normal cartilage, expression of each MMP is tightly regulated. During OA condition, however, MMPs are overexpressed resulting in the degradation of Collagen and other joint tissue-associated proteins necessary for maintaining normal environment of the cartilage. We hypothesize that a set of transcription factors, responsible for the increased expression of MMPs, is present at a higher active level in the chondrocyte cells of OA-cartilage. Consistent with this hypothesis, preliminary studies indicated that chondrocyte cells of the OA joint tissue contain a significantly higher level of several transcription factors, of which one is identified as SAF-1, an inflammation-responsive transcription factor. Over-expression of SAF-1 enhances MMP-1 expression in cultured chondrocyte cells. SAF-1 also interacts with the promoters of MMP-9 and -14 genes indicating its possible role in regulating expression of these MMP genes in OA condition. Identification of the involved transcription factors will provide a molecular basis for regulating their activity for future therapeutic efforts against OA. This research thus focuses on defining the role of SAF-1 in regulating expression of MMP-1, -9 and -14 genes. Another goal of this proposal is to identify other transcription factors involved in this process. Although pathology of OA most likely starts with biomechanical stress on the cartilage, cytokines appear at later stages of the disease. Therefore, an OA-like condition will be created by combining both biomechanical stress and cytokines and mechanisms of MMP gene induction will be studied in response to these signals. Towards this goal, the following specific aims are planned: 1) Characterize the role of SAF-1 in MMP-1 gene induction in chondrocytes of OA-cartilage. Define other responsive elements and factors involved in increasing MMP-1 expression in OA condition. 2) Investigate the role of SAF-1 in the induction of MMP-9 gene expression in OA-cartilage. Identify other regulatory elements and factors involved in this process. 3) Assess the role of SAF-1 in the induction of MMP-1 4 gene and identify other regulatory elements and factors involved in increasing MMP-1 4 expression in chondrocytes under OA-like condition. Completion of the above experimental objectives will form the basis for future investigation on: a) transmembrane signaling pathways in OA chondrocytes that enhance transcriptional activity, and b) evaluation of inhibitors of involved signaling pathway as potential therapeutic agents to control abnormal MMP expression.