Intracellular signal transduction pathways: good therapeutic targets for joint destruction in rheumatoid arthritis.
Preventing joint destruction is one of the most challenging issues in treating patients with rheumatoid arthritis (RA), and I propose that intracellular signaling pathways in osteoclasts and synovial fibroblastic cells (SFCs) can be good therapeutic targets. Osteoclasts are primarily involved in the bone destruction in RA joints, and SFCs support osteoclast differentiation and activation by producing various proinflammatory cytokines including receptor activator of NF-kappaB ligand (RANKL), the osteoclast differentiation factor belonging to the tumor necrosis factor-alpha superfamily. Suppressing c-Src pathways by adenovirus vector-mediated C-terminal Src family kinase (Csk) gene or Ras/extracellular-regulating kinase (ERK) pathways by introducing dominant negative Ras (Ras(DN)) adenovirus reduced osteoclastic bone resorption as well as the abnormal proliferation and interleukin-6 production of SFCs, and the local injection of these viruses ameliorated the joint destruction in adjuvant arthritis rats. Moreover, chondrogenic differentiation of SFCs could be induced by stimulating activin receptor-like kinase 3 pathways.
Tanaka
Sakae
S
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. tanakas-ort@h.u-tokyo.ac.jp