Expression and Tissue Localization of Membrane-Types 1, 2, and 3 Matrix Metalloproteinases in Rheumatoid Synovium

Abstract

SUMMARY:In vitro, membrane-type matrix metalloproteinases (MT-MMP) are known to activate the zymogen of MMP-2 (proMMP-2, progelatinase A), which is one of the key MMP in joint destruction in rheumatoid arthritis. In the present study, we examined the production and activation of proMMP-2, and the expression of MT1-MMP, MT2-MMP, and MT3-MMP, their correlation with proMMP-2 activation, and their localization in rheumatoid synovial tissue. Using sandwich enzyme immunoassay and gelatin zymography techniques, proMMP-2 production levels and activation ratios were found to be significantly higher in rheumatoid synovium compared with normal synovium (p Ͻ 0.01). Quantitative RT-PCR analyses demonstrated that MT1-MMP and MT3-MMP were expressed in all rheumatoid synovial tissue (30 of 30 cases), but that the mean expression level of MT1-MMP was approximately 11-fold higher than MT3-MMP. Significant correlation was found between the mRNA expression level of MT1-MMP and the activation ratio of proMMP-2 (p Ͻ 0.01). In situ hybridization indicated that the hyperplastic lining cells of rheumatoid synovium expressed MT1-MMP. Immunohistochemistry demonstrated that MT1-MMP was co-localized with MMP-2 and with a tissue inhibitor of metalloproteinase-2, and was mainly located in the rheumatoid synovial lining cells. In situ zymography of rheumatoid synovium showed gelatinolytic activity, predominantly in the lining cell layer. This activity was blocked when incubated with BB94, a specific MMP inhibitor. These results demonstrate that MT1-MMP plays an important role in the activation of proMMP-2 in the rheumatoid synovial lining cell layer, and suggest that its activity may be involved in the cartilage destruction of rheumatoid arthritis. (Lab Invest 2000, 80:677-687).

Inhibition of furin‐like enzymes blocks interleukin‐1α/oncostatin M–stimulated cartilage degradation

“…These MT-MMPs are present in rheumatoid and osteoarthritic tissues (53)(54)(55). MT1-MMP can cleave type II collagen (13), which is the major type of collagen in articular cartilage.…”

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

“…Indeed, more than 30 y ago, Werb et al (30) and colleagues first demonstrated that human RA synoviocytes cultured under serum-free conditions and supplemented with plasminogen were able to mount potent collagenolytic activity. Although the relative roles of MMP-1 versus MMP-13 were not assessed in this model (MMP- 13 had not yet been identified), the issue of how the collagenase zymogen(s) might undergo extracellular activation in the presence of a relative excess of plasma antiproteinases was considered (30). In their study, the authors postulated that synoviocytes "penetrate" the antiproteinase shield by generating quantities of proteinases that exceed the local concentration of proteinase inhibitors (e.g., plasma proteinase inhibitors directed against plasmin or MMP-1, a 2 -antiplasmin, and TlMP-1, respectively, bind and inhibit target proteinases at a 1:1 molar ratio) (30,43).…”

“…Further, like the MMP family, the cysteine proteinases also comprise a large group of proteolytic enzymes, but only a single member of this gene family, termed cathepsin K, displays triplehelical collagenolytic properties (7,8). Significantly, all seven of these collagenases have been identified in the rheumatoid synovium at the mRNA or protein levels, or both (10)(11)(12)(13)(14)(15)(16)(17)(18)(19). The precise role, however, that these enzymes play in RA synoviocyte-mediated tissue destruction remains the subject of speculation.…”

Synovial fluid exoglycosidases are predictors of rheumatoid arthritis and are effective in cartilage glycosaminoglycan depletion

“…MT-MMP-1 and MT-MMP-3 in particular have been detected at sites of destruction in rheumatoid arthritis (RA) (7,8). Several of these enzymes are currently considered therapeutic targets in arthritic diseases.…”