ACTIVATION OF CHONDROCYTE MATURATION IN OSTEOARTHRITIS

在与骨关节炎相关的软骨退化期间， 软骨细胞增殖（克隆）、肥大和钙化 发生，类似于发生期间发生的事件的重演 软骨内骨形成 最近，一些新的基因， 在软骨细胞成熟过程中表达已经被表征， 包括PTHrP、PTH/PTHrP受体、印度刺猬（IHH）、膜联蛋白V， BMP6 我们还鉴定了NHE 1（Na+/H+交换器亚型）， PTHrP和BMP 6调控下的候选分子，其驱动 软骨细胞肥大体积增加。 我们已经鉴定出PTHrP， 骨形成蛋白6在正常成人关节软骨中不表达， 人OA软骨。 这导致了我们的总体假设， OA中细胞因子的产生导致软骨细胞的活化 成熟途径 这一途径的要素，包括细胞 增殖、MMP产生、肥大、基质周转和 细胞凋亡，可能有助于OA的病理生理学。 理解 因此，成熟途径的调节可能导致新的 OA的诊断标志物或治疗靶点。 具体目标1将 使用良好表征的体外软骨细胞培养模型来研究 IHH，PTHrP和PRHrP受体在启动 成熟 具体目标2将检查TNF和其他 细胞因子对软骨成熟相关基因表达的影响。 具体目标3将使体外结果与基于组织的 使用TNF过表达的鼠软骨细胞成熟的研究 关节炎模型和人OA软骨。 因此，本提案将研究BMP之间的相互关系， 甲状旁腺素受体P及其协同作用对软骨细胞的调节 在软骨内骨化过程中成熟。

During cartilage degeneration associated with osteoarthritis, chondrocyte proliferation (cloning), hypertrophy, and calcification occur, resembling a recapitulation of the events which occur during endochondral bone formation. Recently a number of new genes which are expressed during chondrocyte maturation have been characterized, including PTHrP, PTH/PTHrP receptor, indian hedgehog (IHH), annexin V, and BMP6. We have also identified NHE1 (a Na+/H+ exchanger isoform) as a candidate molecule under regulation of PTHrP and BMP6 which drives the chondrocyte hypertrophic volume increase. We have identified PTHrP and BMP6, which are not expressed in normal adult articular cartilage, in human OA cartilage. This has led to our overall hypothesis that cytokine production in OA leads to activation of the chondrocyte maturation pathway. Elements of this pathway, including cell proliferation, MMP production, hypertrophy, matrix turnover, and apoptosis, may contribute to the pathophysiology of OA. Understanding the regulation of the maturational pathway may therefore lead to new diagnostic markers or therapeutic targets in OA. Specific Aim 1 will use well characterized in vitro chondrocyte culture models to study the role of IHH, PTHrP, and the PRHrP receptor in the initiation of maturation. Specific Aim 2 will examine the effect of TNF and other cytokines on gene expression associated with chondrctye maturation. Specific Aim 3 will correlate the in vitro findings with tissue-based studies of chondrocyte maturation using a TNF overexpression murine arthritis model, and human OA cartilage. Thus, this proposal will examine the inter-relationships between BMPs, PTHrP and their coordinate role in the regulation of chondrocyte maturation during endochondral ossification.