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)是最常见的关节炎。它发生了 几乎在老年人中普遍存在，并导致严重残疾 超过20%的患者。最近的调查表明 能够进行实验测试的病理生理途径。它是 假设，在一次未知的初级侮辱之后，激活了 蛋白水解酶降解细胞外基质成分，包括 蛋白多糖和胶原蛋白。降解之后是软骨细胞 增殖和合成修复。在这方面拟议的进口机制 白介素1最终激活的释放途径 蛋白水解酶。生长肽，如胰岛素样生长 胰岛素样生长因子-1(IGF-1)可能在合成和转化过程中发挥重要作用。 增殖的细胞试图修复。我们的研究将测试 假设骨质疏松症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。总体目标将是研究 利用cDNA探针和分子技术研究骨性关节炎病理生理学中的时间事件 明确的半月板部分切除模型中的杂交技术。 此模型的可用性使我们能够更精确地分析这些 互动。目的L将定义软骨细胞稳态信使核糖核酸 蛋白多糖聚集单体(Aggrecan)、链接蛋白、 基质分解素、胶原酶和白细胞介素2-L； 与基质和酶基因的最终产物反应相关； 病理生理机制将进一步评估使用 白介素1受体拮抗剂(IL-1RA)和前列腺素-EL类似物。 目标2将研究生长肽及其受体(IGF-1)的反应 及其I型受体；和生长激素受体)。这些 建议进行调查，以进一步了解 骨性关节炎的病理生理学机制及其潜在的疾病调控作用 使用特定的治疗方法。