ACTIVATION OF CHONDROCYTE MATURATION IN OSTEOARTHRITIS

在与骨关节炎相关的软骨退化过程中， 软骨细胞增殖(克隆)、肥大和钙化 发生，类似于对发生在 软骨内骨形成。最近出现了一些新基因，它们是 在软骨细胞成熟过程中表达的基因已经被表征， 包括甲状旁腺素受体、甲状旁腺素/甲状旁腺素受体、印度刺猬、膜联蛋白V、 和Bmp6。我们还鉴定了NHE1(一种Na+/H+交换异构体)为 PTHrP和Bmp6调控下的候选分子，驱动 软骨细胞肥大体积增大。我们已经确定了PTHrP和 Bmp6在正常成人关节软骨中不表达，在 人骨关节炎软骨。这导致了我们的总体假设 细胞因子在骨关节炎中的产生导致软骨细胞的激活 成熟途径。这一途径的要素，包括细胞 增殖、基质金属蛋白酶的产生、肥大、基质周转和 细胞凋亡，可能参与了骨性关节炎的病理生理过程。理解 因此，对成熟途径的调节可能会导致新的 骨关节炎的诊断标记物或治疗靶点。具体目标1将 利用体外软骨细胞培养模型研究软骨细胞的体外培养 IHH、PTHrP和PRHrP受体在促性腺激素释放中的作用 成熟。具体目标2将检查肿瘤坏死因子和其他 细胞因子对软骨成熟相关基因表达的影响。 特殊目标3将把体外研究结果与基于组织的研究结果联系起来 肿瘤坏死因子高表达小鼠软骨细胞成熟的研究 关节炎模型和人骨性关节炎软骨。 因此，本提案将审查BMP之间的相互关系， 甲状旁腺素受体及其在软骨细胞调控中的协同作用 软骨内骨化过程中的成熟。

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.