METABOLISM IN NORMAL AND OSTEOARTHRITIC CARTILAGE

描述（改编自申请人的摘要）：骨关节炎（OA）是 一种常见的致残性关节疾病，主要折磨老年人。 一 关节面的进行性破坏是由于 软骨内的蛋白水解活性。 申请人的实验室拥有 提供了一种新的蛋白酶，MMP酶原激活剂（MMP-PA）， 其激活MMP-3（基质溶解素）和MMP-9（92 k明胶酶）。 MMP-PA是 由关节软骨产生，可以作为一个重要的调节器， MMP在该组织的发育、生长和修复过程中的活性。 申请人的研究还导致了丝氨酸的发现 由软骨产生的蛋白酶，可抑制组织抑制剂， 金属蛋白酶（TIMPs）。 因此，这两个组成部分， 由软骨合成，构成一个内源性系统，可能 是组织蛋白水解的关键决定因素。 检验假设 OA中这些蛋白酶的过度表达破坏了 细胞外基质降解酶的级联反应， 软骨破坏 该提案的目标是净化 MMP-PA和TIMP-裂解蛋白酶，以及cDNA克隆的分离。 MMP-PA 不仅激活MMP-3和MMP-9， 在软骨中形成级联。 因此，提出实验来确定 MMP-PA是否刺激软骨中的聚集蛋白聚糖酶样活性。 TIMP 将检查OA软骨中的catenin的末端氨基酸 与TIMP-裂解酶的体内作用一致的序列。 是 表明，通过特异性抑制软骨中的这些酶， 对于OA患者，将产生细胞外基质的净增加。 是 进一步推测，OA产生的丝氨酸蛋白酶的研究 软骨可能对这种管理有很大的影响， 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.