Role and Regulation of ADAMTS-12 in the Cartilage Catabolism

ADAMTS-12 在软骨分解代谢中的作用和调节

• 批准号: 7493578
• 负责人: Chuanju Liu
• 金额: $ 6.81万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7493578
• 关键词: ADAMTS; Arthritis; Binding; Biological; Biological Assay; Biological Markers; Blocking Antibodies; Cartilage; Catabolism; Catalytic Domain; Cells; Cessation of life; Chondrocytes; Data; Degenerative polyarthritis; Depth; Development; Digestion; Disease; Disintegrins; Early Intervention; Elderly; Enzymes; Event; Extracellular Matrix; Extracellular Matrix Degradation; Family; Foundations; Genetic Screening; In Vitro; Interstitial Collagenase; Investigation; Joints; Kinetics; Laboratories; Matrix Metalloproteinases; Mediating; Metalloproteases; Metals; Molecular; Monitor; N-terminal; PC cell-derived growth factor; Patients; Pattern; Physiological; Process; Progranulin; Property; Protein Binding; Protein Binding Domain; Proteolysis; RNA; Range; Recruitment Activity; Regulation; Research; Role; Site; Structure; Subgroup; Synovial Membrane; Testing; Tissue Inhibitor of Metalloproteinases; Tissues; Work; Zinc; alpha 2-Glucoproteins; analog; articular cartilage; cartilage metabolism; collagenase 3; granulin; in vivo; inhibitor/antagonist; mammalian COMP; member; mutant; novel; prevent; protein degradation; research study

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a degenerative joint disease that occurs primarily in older persons and is characterized by erosion of the articular cartilage and breakdown of extracellular matrix. Cartilage oligomeric matrix protein (COMP), a noncollagenous matrix component whose prominent degradative fragments have been observed in arthritic patients, shows great promise as a biological marker of cartilage metabolism. The molecular mechanism of COMP degradation and the enzyme(s) responsible for it, however, remain largely unknown. Recent work in our laboratory using a functional genetic screen identified the zinc-metalloproteinase ADAMTS- 7 (ADAMTS: a disintegrin and metalloproteinase with thrombospondin motifs) as the first COMP-binding enzyme. Subsequent sequence and structure analyses revealed that ADAMTS-12 has a domain organization similar to that of ADAMTS-7 and that the two enzymes form a subgroup with unique properties within the ADAMTS family. These findings, along with the fact that ADAMTS-12, and not ADAMTS-7, is significantly upregulated in the OA cartilage, provide a foundation for our hypothesis that ADAMTS-12 is the major physiological enzyme responsible for COMP degradation in OA. The specific aims of the proposed study are (1) to characterize the degradation of COMP by ADAMTS-12 and to identify its cleavage sites; and (2) to identify and characterize the naturally occurring inhibitors of ADAMTS-12. The proposed research will provide new information towards understanding the molecular mechanism of cartilage catabolism, and thusly, aid in the development of novel treatment regimes for the management of OA by directly applying inhibitors of ADAMTS-12 or its analogs.

描述(申请人提供)：骨关节炎(OA)是一种退行性关节疾病，主要发生在老年人，以关节软骨侵蚀和细胞外基质破坏为特征。软骨低聚基质蛋白(COMP)是一种非胶原性基质成分，在关节炎患者中已观察到其显著的降解片段，作为软骨代谢的生物标志显示出巨大的前景。然而，COMP降解的分子机制和负责它的酶(S)仍然很大程度上是未知的。我们实验室最近利用功能遗传学筛选的方法确定锌-金属蛋白酶ADAMTS-7(ADAMTS：一种带有凝血酶反应蛋白基序的去整合素和金属蛋白酶)是第一个COMP结合酶。随后的序列和结构分析表明，ADAMTS-12具有与ADAMTS-7相似的结构域组织，这两种酶在ADAMTS家族中形成了一个具有独特性质的亚群。这些发现，以及ADAMTS-12而不是ADAMTS-7在骨性关节炎软骨中显著上调的事实，为我们的假设提供了基础，即ADAMTS-12是导致骨性关节炎COMP降解的主要生理酶。拟议研究的具体目的是(1)表征ADAMTS-12对COMP的降解并确定其切割位点；(2)鉴定和表征ADAMTS-12的天然抑制剂。这项研究将为了解软骨分解代谢的分子机制提供新的信息，从而有助于开发通过直接应用ADAMTS-12或其类似物的抑制剂来治疗骨性关节炎的新的治疗方案。