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 identify 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.
Sabeh
Farideh
F
Division of Molecular Medicine and Genetics, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Fox
David
D
Weiss
Stephen J
SJ
D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism
C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14