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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan.
M
M
Tsuji
K
K
Hirakawa
A
A
Kato
K
K
Fujii
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D019902:Chondrocytes / Q000378:metabolism; D002813:Chondrosarcoma; D003094:Collagen / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D003094:Collagen; D020781:Matrix Metalloproteinase 1