Membrane-Type I Matrix Metalloproteinase-Dependent Regulation of Rheumatoid Arthritis Synoviocyte Function

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.