METABOLISM IN NORMAL AND OSTEOARTHRITIC CARTILAGE

描述(摘自申请者摘要)：骨性关节炎(OA) 一种常见的致残性关节疾病，主要折磨老年人。一个 关节表面的进行性破坏是由于 软骨内的蛋白质分解活性。申请人的实验室有 提供了一种新型蛋白酶--基质金属蛋白酶原激活物(MMPPA)的证据， 激活基质分解蛋白-3(基质分解酶)和基质金属蛋白酶-9(92K明胶酶)。基质金属蛋白酶-PA是 由关节软骨产生，可能是一种重要的调节因子 基质金属蛋白酶在发育、生长和修复过程中的活性。 申请人的研究也导致了丝氨酸的发现 S：由软骨产生的使组织抑制物失活的蛋白酶(S) 金属蛋白酶(TIMPs)。因此，这两个组件，即 由软骨合成，构成一个内源性系统，很可能 是组织蛋白分解的关键决定因素。检验假设是 这些蛋白水解酶在骨性关节炎中的过度表达扰乱了严格的调控 细胞外基质降解酶的级联反应，最终导致 软骨破坏。这项提议的目标是净化 裂解MMPPA和TIMP的蛋白水解酶以及克隆的克隆。基质金属蛋白酶-PA 不仅激活了基质金属蛋白酶-3和基质金属蛋白酶-9，而且可能激活了整个降解物 在软骨中发生级联。因此，建议进行实验以确定 基质金属蛋白酶-PA是否刺激软骨中侵袭性葡聚糖酶样活性。TIMP 将检查骨性关节炎软骨中的分解代谢产物的末端氨基酸 序列与TIMP裂解酶在体内的作用一致(S)。它是 提示通过特异性地抑制软骨中的这些酶 对于OA患者，细胞外基质的净收益将被创造出来。它是 进一步推测，OA产生的丝氨酸蛋白酶的研究 软骨可能对这一疾病的处理有很大的影响。 使人衰弱的疾病。

DESCRIPTION (Adapted from the Applicant's Abstract): Osteoarthritis (OA) is a common disabling joint disease that principally afflicts the elderly. A progressive destruction of the articular surface results from increased proteolytic activity within the cartilage. The applicant's laboratory has provided evidence of a novel proteinase, MMP proenzyme activator (MMP-PA), which activates MMP-3 (stromelysin) and MMP-9 (92k gelatinase). MMP-PA is produced by articular cartilage and may serve as an important regulator of MMP activity in this tissue in processes of development, growth and repair. The applicant's studies have also led to the discovery of serine proteinase(s) produced by cartilage that inactivate the tissue inhibitors of metalloproteinases (TIMPs). Thus, these two components, that are synthesized by cartilage, constitute an endogenous system that is likely to be a critical determinant of tissue proteolysis. The test hypothesis is that overexpression of these proteinases in OA disrupts the tight regulation of a cascade of extracellular matrix degrading enzymes, ultimately causing cartilage destruction. The goals of this proposal are the purification of MMP-PA and TIMP-cleaving proteinases, and isolation of cDNA clones. MMP-PA activates not only MMP-3 and MMP-9, but perhaps an entire degradative cascade in cartilage. Experiments are therefore proposed to determine whether MMP-PA stimulates aggrecanase-like activity in cartilage. TIMP catabolites in OA cartilage will be examined for terminal amino acid sequences consistent with in vivo action of TIMP-cleaving enzyme(s). It is suggested that by specifically inhibiting these enzymes in the cartilage of OA patients, a net gain in extracellular matrix will be created. It is further speculated that the study of serine proteinases produced by OA cartilage may have strong implications for the management of this debilitating disease.