Osteoporosis in rheumatoid arthritis: a molecular biological aspect of connective tissue gene activation.
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.
Shiozawa
S
S
Department of Medicine, 3rd Division, Kobe University School of Medicine, Japan.
Kuroki
Y
Y
D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000235:genetics*; D003238:Connective Tissue / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology; D010024:Osteoporosis / Q000209:etiology*; D011458:Prostaglandins E / Q000502:physiology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D007375:Interleukin-1; D011458:Prostaglandins E; D014409:Tumor Necrosis Factor-alpha