Abstract
Osteoporosis, especially the juxtaarticular osteoporosis of involved joints is characteristic to rheumatoid arthritis (RA) . Histomorphometric studies suggest the existence of increased bone turnover in RA: impaired bone formation and hightened osteoclastic bone resorption. Recent studies show that important mediators in the pathogenesis of RA, such as prostaglandin E, interleukin 1 (IL-1) or tumor necrosis factor α (TNF α), are also important in the bone remodelling and, more importantly, the signal transduction mediated by these IL-1 or TNF α is tightly associated with the activation of c-fos gene and related AP 1 regulated gene expression.
We have shown that constitutive expression of c-fos gene in transgenic mice results in the joint destruction solely by the synovial mesenchymal cells. A transfection study shows that constitutive expression of c-fos gene in rheumatoid synovial cells supports the growth and morphological transformation of these cells. Because c-fos expression is indeed enhanced in rheumatoid synovia, we studied the effects of c-fos on MC3T3-E1 osteoblasts by the transfection technique. The results show that the percent collagen synthesis as well as type I collagen mRNA expression was significantly depressed in c-fos-expressing transfectants. The culture supernatants of c-fos-expressing osteoblasts significantly enhanced the generation of mature osteoclasts from precursor cells and facilitated osteoclastic bone resorption as examined with the pit formation technique.
The results therefore suggest that constitutive expression of c-fos DNA facilitates synovial cell growth and interferes with bone formation by inhibiting collagen synthesis in osteoblasts and bone resorption by osteoclasts, and in this way a reminiscent feature to human RA is experimentally reproduced.
