The possible role of c-fos expression in rheumatoid cartilage destruction.

Abstract

To determine the effect of c-fos on human chondrocytes and to examine the role of c-fos in cartilage destruction in rheumatoid arthritis (RA). We examined changes in collagen synthesis by transfecting human c-fos into cultured human chondrocytes and evaluated expression of c-fos mRNA and localization of Type II collagen, matrix metalloproteinases-1 (MMP-1), and tissue inhibitor of metalloproteinases-1 (TIMP-1) in articular cartilage samples from patients with RA or osteoarthritis (OA) by in situ hybridization and immunohistochemistry. Introduction of c-fos in the chondrocytes decreased endogenous transcription of Type II collagen and TIMP-1, and increased that of MMP-1. The effect of the activating protein-1 protein on the MMP-1 and TIMP-1 promoters in human articular chondrocytes was analyzed by chloramphenicol acetyltransferase activity assay. MMP-1 promoter was clearly activated by Jun related proteins as well as Fos/Jun related protein heterocomplex. On the other hand, c-fos combined with any of the Jun related proteins failed to stimulate the TIMP-1 promoter, although it was activated by Fra-1 or Fra-2/Jun related protein heterocomplexes. Expression of c-fos mRNA was detected in chondrocytes in the mid and deep layers of cartilage in 11/15 patients (73%) with RA, but only in the superficial layer of cartilage from 2/10 patients (20%) with OA. Although TIMP-1 staining exceeded that of MMP-1 in OA cartilage, it appeared to be less intense than MMP-1 staining in RA cartilage. These results suggest that activation of c-fos may be involved in cartilage metabolism and hence play a crucial role in the pathogenesis of arthritic destruction in RA.