ABSTRACT
Matrix metalloproteinases (MMPs) contribute to the joint damage in rheumatoid arthritis (RA). Less is known of the involvement of MMPs at extra-articular sites of rheumatoid inflammation. We assessed the relative contribution from MMP-1, MMP-3, MMP-7 and MMP-12 to joint and extra-articular tissue destruction and inflammation by comparing gene expression in joint synovia and subcutaneous rheumatoid nodules from RA patients. Expression of MMP-1 and MMP-3 predominated in synovia, whereas MMP-12 expression was significantly higher in rheumatoid nodules. Markedly higher MMP-7 expression distinguished a subgroup of nodules that featured infiltrating monocyte/macrophage-producing MMP-7 protein. The high MMP-7 expression in nodules was associated with the single-nucleotide polymorphism (SNP) rs11568818 (-181A>G, MMP-7 promoter) and more active inflammation within the nodule lesions. Patients with such nodules had significantly earlier age of RA onset. Our findings indicate that the expression of MMP-1 and MMP-3 occurs relatively independent of the tissue microenvironment with substantial expression also at extra-articular sites. MMP-12 expression reflects the involvement of monocyte/macrophages in rheumatoid inflammation. Evidence for the association between the rs11568818 SNP and increased MMP-7 expression is restricted to nodules, which indicates that consequences of the MMP-7 polymorphism are likely to manifest within aspects of immune/inflammatory activity that are monocyte/macrophage-mediated.
