Osteoporosis in Rheumatoid Arthritis: A Molecular Biological Aspect of Connective Tissue Gene Activation.

Abstract

Osteoporosis, especially the juxtaarticular osteoporosis of involved joints, is a characteristic manifestation of rheumatoid arthritis (RA). Histomorphometric studies suggest the existence of increased bone turnover in RA: impaired bone formation and hightened osteoclasic bone resorption. Recent studies show that important mediators in the pathogenesis of RA such as prostaglandin E, interleukin 1 (IL1) or tumor necrosis factor (TNF) alpha also play important roles in bone remodelling. Prostaglandin E2 promotes maturation of osteoclasts from hematopoietic precursor cells. IL1 inhibits collagen synthesis in osteoblasts. IL1 enhances collagenase and stromelysin gene expression and stimulates osteoclastic bone resorption. TNF alpha inhibits bone collagen synthesis and causes osteoclastic bone resorption. TNF alpha, and possibly IL1, enhances collagenase and stromelysin gene expression by stimulating the AP-1 promoter sites of the genes. Constitutive expression of c-fos induces joint destruction without lymphocyte infiltration in antigen-induced arthritis in mice, and supports cell growth of human rheumatoid synovial cells, possibly acting on the AP-1 sites. Furthermore, constitutive c-fos expression decreases collagen synthesis in osteoblasts and increases the mediator secretion from osteoblasts thereby stimulating osteoclastic bone resorption. These findings suggest that signal transduction through AP-1 transcriptional regulation sites may play an important role in the pathogenesis of joint destruction and osteoporosis in RA.

Pathogenesis of Joint Destruction in Rheumatoid Arthritis

“…Osteoclastic bone resorption is characteristically seen very early in the disease at the peri-articular areas of the bone of patients with RA (Shimizu et al 1985;Shiozawa and Kuroki 1994), and can be a very early sign of RA clinically. Molecular studies show that differentiation of osteoclast is facilitated in four ways (Takayanagi 2007;Theill et al 2002;Walsh et al 2006).…”

“…Instead, IL-1b facilitates osteoclast formation and significantly enhance RANKL-induced osteoclastogenesis (Jiang et al 2000;Shiozawa and Kuroki 1994;Zwerina et al 2007). A total lack of chronic erosive arthritis is noted in IL-1b-deficient mice (Gravallese and Goldring 2000), and even the arthritic joint destruction of TNF-a transgenic mice can be totally inhibited by anti-IL-1 receptor antibody in face of still increased serum TNF-a (Probert et al 1995).…”