ACTIVATION OF CHONDROCYTE MATURATION IN OSTEOARTHRITIS

骨关节炎中软骨细胞成熟的激活

• 批准号: 6137336
• 负责人: RANDY N ROSIER
• 金额: $ 28.62万
• 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/6137336
• 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变性过程中 软骨细胞增殖（克隆），肥大和钙化 发生，类似于对事件发生的事件的概括 软骨骨形成。 最近有许多新基因 在软骨细胞成熟期间表达 包括PTHRP，PTH/PTHRP受体，印度刺猬（IHH），Annexin V， 和BMP6。 我们还将NHE1（Na+/H+交换器同工型）确定为 PTHRP和BMP6调节的候选分子，该分子驱动 软骨细胞肥厚量增加。 我们已经确定了PTHRP和 BMP6在正常成人关节软骨中未表达，在 人OA软骨。 这导致了我们的总体假设 OA中的细胞因子产生导致软骨细胞的激活 成熟途径。 该途径的元素，包括细胞 增殖，MMP产生，肥大，基质周转和 凋亡可能有助于OA的病理生理。 理解 因此，成熟途径的调节可能导致新的 OA中的诊断标记或治疗靶标。 具体目标1将 使用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。 特定的目标2将检查TNF和其他的效果 与软骨成熟相关的基因表达的细胞因子。 特定的目标3将与基于组织的体外发现相关 使用TNF过表达鼠的软骨细胞成熟的研究 关节炎模型和人OA软骨。 因此，该建议将检查BMP之间的相互关系， PTHRP及其在软骨细胞调节中的协调作用 内软骨骨化过程中的成熟。