ACTIVATION OF CHONDROCYTE MATURATION IN OSTEOARTHRITIS

骨关节炎中软骨细胞成熟的激活

• 批准号: 6341789
• 负责人: RANDY N ROSIER
• 金额: $ 28.2万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-15 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6341789
• 关键词: RNase protection assay; SDS polyacrylamide gel electrophoresis; articular cartilage; biomarker; bone morphogenetic proteins; cartilage development; chickens; chondrocytes; cytokine; digital imaging; fluorescence microscopy; gene expression; growth factor receptors; human tissue; in situ hybridization; laboratory mouse; molecular cloning; normal ossification; northern blottings; osteoarthritis; parathyroid hormone related protein; polymerase chain reaction; receptor expression; statistics /biometry; tumor necrosis factor alpha; western blottings

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.

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，类似于在期间发生的事件的重述 软骨内骨形成。 最近出现了一些新基因 在软骨细胞成熟过程中表达的特征已被表征， 包括 PTHrP、PTH/PTHrP 受体、印度刺猬 (IHH)、膜联蛋白 V、 和 BMP6。 我们还确定了 NHE1（Na+/H+ 交换异构体）为 受 PTHrP 和 BMP6 调节的候选分子，驱动 软骨细胞肥大体积增加。 我们已经确定了 PTHrP 和 BMP6 在正常成人关节软骨中不表达， 人类骨关节炎软骨。 这导致我们的总体假设是 OA 中细胞因子的产生导致软骨细胞活化 成熟途径。 该途径的元件，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会导致新的 OA 的诊断标志物或治疗靶点。 具体目标 1 将 使用特征良好的体外软骨细胞培养模型来研究 IHH、PTHrP 和 PRHrP 受体在启动中的作用 成熟。 具体目标 2 将检查 TNF 和其他物质的作用 细胞因子对与软骨成熟相关的基因表达的影响。 具体目标 3 将体外研究结果与基于组织的结果相关联 使用 TNF 过表达小鼠进行软骨细胞成熟研究 关节炎模型和人类 OA 软骨。 因此，该提案将审查 BMP 之间的相互关系， PTHrP及其在软骨细胞调节中的协调作用 软骨内骨化过程中的成熟。