PATHOGENESIS AND THERAPY OF EXPERIMENTAL OSTEOARTHRITIS

实验性骨关节炎的发病机制和治疗

• 批准号: 2078678
• 负责人: ROLAND W MOSKOWITZ
• 金额: $ 18.49万
• 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/2078678
• 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）是关节炎最常见的形式。 它发生 在老年人中几乎普遍存在，并导致严重残疾， 超过20%的患者。 最近的调查显示 病理生理途径能够进行实验测试。 是 假设，在未知的原发性损伤后， 蛋白水解酶降解细胞外基质组分， 蛋白聚糖和胶原蛋白。 降解后是软骨细胞 增殖和合成修复。 在这方面拟议的进口机制 与最终激活白细胞介素-1（IL-1）释放有关的途径 蛋白水解酶。 生长肽，如胰岛素样生长 因子-1（IGF-1）可能在合成和 增殖细胞修复的尝试。 我们的研究将测试 假设OA与蛋白水解酶的释放有关， 对细胞因子的反应，随后是合成修复反应 与生长肽有关。 总体目标是研究 利用cDNA探针和分子生物学技术， 杂交技术在明确定义的部分直肠癌切除术模型。 该模型的可用性允许对这些进行更精确的分析 相互作用 目的：确定软骨细胞稳态信使RNA 蛋白聚糖聚集单体（聚集蛋白聚糖），连接蛋白， 基质溶解素、胶原酶和白细胞介素-1; mRNA结果将在 与基质和酶基因终产物反应相关; 将进一步评估病理生理机制， 白细胞介素-1受体拮抗剂（IL-1 RA）和白细胞介素-El类似物。 目的2研究生长肽及其受体（IGF-1）对胰岛素抵抗的影响 及其I型受体;和生长激素受体）。 这些 提出调查作为进一步了解 OA病理生理学机制，具有疾病调节潜力 使用特定的治疗方法。