Membrane-Type I Matrix Metalloproteinase-Dependent Regulation of Rheumatoid Arthritis Synoviocyte Function
Membrane-Type I Matrix Metalloproteinase-Dependent Regulation of Rheumatoid Arthritis Synoviocyte Function
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DOI：
10.4049/jimmunol.0904068
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发表时间：
2010-06-01
影响因子：
4.4
通讯作者：
Weiss, Stephen J.
中科院分区：
文献类型：
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作者：
Sabeh, Farideh;Fox, David;Weiss, Stephen J.
在类风湿性关节炎中，滑膜细胞团块的协调扩张与病理性血管生成反应相结合，导致关节及其周围结缔组织的破坏性重塑。虽然类风湿滑膜细胞表达多种蛋白水解酶，但软骨、韧带和肌腱损伤的主要影响因子仍不明确。在此，我们证明了人类类风湿滑膜细胞动员膜锚定基质金属蛋白酶（MMP），膜I型MMP (MT1-MMP)，溶解和侵入I型和II型胶原蛋白丰富的组织。虽然类风湿滑膜细胞也表达一系列分泌的胶原酶，但在血浆或滑膜液衍生的抗蛋白酶的生理浓度存在时，这些蛋白酶在介导胶原溶解活性方面是无效的。此外，MT1-MMP不仅指导类风湿性滑膜细胞的组织破坏特性，而且还控制体内滑膜细胞启动的血管生成反应。总之，这些发现确定了MT1-MMP是病理性细胞外基质重塑的主要调节因子，类风湿关节炎的特征以及维持进展性血管炎侵袭性表型的耦合血管生成反应。免疫学杂志，2010,18(4):696 - 696。
In rheumatoid arthritis, the coordinated expansion of the synoviocyte mass is coupled with a pathologic angiogenic response that leads to the destructive remodeling of articular as well as surrounding connective tissues. Although rheumatoid synoviocytes express a multiplicity of proteolytic enzymes, the primary effectors of cartilage, ligament, and tendon damage remain undefined. Herein, we demonstrate that human rheumatoid synoviocytes mobilize the membrane-anchored matrix metalloproteinase (MMP), membrane-type I MMP (MT1-MMP), to dissolve and invade type I and type II collagen-rich tissues. Though rheumatoid synoviocytes also express a series of secreted collagenases, these proteinases are ineffective in mediating collagenolytic activity in the presence of physiologic concentrations of plasma-or synovial fluid-derived antiproteinases. Furthermore, MT1-MMP not only directs the tissue-destructive properties of rheumatoid synoviocytes but also controls synoviocyte-initiated angiogenic responses in vivo. Together, these findings indentify MT1-MMP as a master regulator of the pathologic extracellular matrix remodeling that characterizes rheumatoid arthritis as well as the coupled angiogenic response that maintains the aggressive phenotype of the advancing pannus. The Journal of Immunology, 2010, 184: 6396-6406.