PATHOGENESIS AND THERAPY OF EXPERIMENTAL OSTEOARTHRITIS

实验性骨关节炎的发病机制和治疗

• 批准号: 2078679
• 负责人: ROLAND W MOSKOWITZ
• 金额: $ 19.06万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-20 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2078679
• 关键词: chondrocytes; collagenase; cytokine receptors; disease /disorder model; endopeptidases; genetic regulation; growth factor receptors; insulinlike growth factor; interleukin 1; laboratory rabbit; messenger RNA; molecular pathology; nucleic acid hybridization; nucleic acid probes; osteoarthritis; prostaglandin analogs; proteoglycan; stromelysin

Osteoarthritis (OA) is the most common form of arthritis. It occurs almost universally in the aged, and results in significant disability in over 20% of patients. Recent investigations have suggested pathophysiologic pathways capable of experimental testing. It is postulated that, following an as yet unknown primary insult, activation of proteolytic enzymes degrades extracellular matrix components including proteoglycan and collagen. Degradation is followed by chondrocyte proliferation and synthetic repair. Mechanisms of proposed import in this pathway relate to release of interleukin-l (IL-1) with eventual activation of proteolytic enzymes. Growth peptides such as insulin-like growth factor-1 (IGF-1) likely play an important role in synthetic and proliferative cellular attempts at repair. Our studies will test the hypothesis that OA is associated with release of proteolytic enzymes in response to cytokines, followed sequentially by synthetic repair responses associated with growth peptides. The overall goal will be to study temporal events in OA pathophysiology, utilizing cDNA probes and molecular hybridization techniques in the well-defined partial meniscectomy model. The availability of this model allows a more precise analysis of these interplays. Aim l will define chondrocyte steady-state messenger RNA levels for proteoglycan aggregating monomer (aggrecan), link protein, stromelysin, collagenase and interleukin-l; mRNA findings will be correlated with matrix and enzyme gene end-product responses; pathophysiologic mechanisms will be further assessed utilizing an interleukin-l receptor antagonist (IL-1 RA) and a prostaglandin-El analog. Aim 2 will study responses of growth peptides and their receptors (IGF-1 and its type I receptor; and growth hormone receptor). These investigations are proposed as an approach to further understand mechanisms of OA pathophysiology, with potential for disease modulation using specific therapeutic approaches.

骨关节炎（OA）是关节炎的最常见形式。 它发生 几乎普遍在老年中，并导致严重的残疾 超过20％的患者。 最近的调查表明 能够实验测试的病理生理途径。 这是 假设，在尚未确定的主要侮辱之后，激活 蛋白水解酶降解细胞外基质成分，包括 蛋白聚糖和胶原蛋白。 降解之后是软骨细胞 增殖和合成修复。 拟议进口的机制 途径与白介素L（IL-1）的释放有关，最终激活 蛋白水解酶。 生长肽，例如胰岛素样生长 因子1（IGF-1）可能在合成和 增殖性细胞尝试进行修复。 我们的研究将测试 OA与蛋白水解酶释放有关的假设 对细胞因子的反应，然后顺序进行合成修复反应 与生长肽有关。 总体目标是学习 OA病理生理学的时间事件，利用cDNA探针和分子 定义明确的部分半月板切除术模型中的杂交技术。 该模型的可用性允许对这些模型进行更精确的分析 互动。 AIM L将定义软骨细胞稳态Messenger RNA 蛋白聚糖聚集单体（aggrecan），链接蛋白质的水平， Stromelysin，胶原酶和白介素L； mRNA发现将是 与基质和酶基因最终产物反应相关； 通过使用一种病理生理机制，将进一步评估 白介素L受体拮抗剂（IL-1 RA）和前列腺素-EL类似物。 AIM 2将研究生长肽及其受体的反应（IGF-1 及其I型受体；和生长激素受体）。 这些 提出调查是一种进一步理解的方法 OA病理生理学的机制，具有疾病调节的潜力 使用特定的治疗方法。