J. Clin. Invest. 110:1419-1427 (2002). doi:10.1172/JCI200215582.
Copyright ©2002 by the American Society for Clinical Investigation
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Article
Osteoclasts are essential for TNF-–mediated joint destruction
Kurt Redlich1, Silvia Hayer2, Romeo Ricci3, Jean-Pierre David3, Makiyeh Tohidast-Akrad4, George Kollias5, Günter Steiner1, Josef S. Smolen1, Erwin F. Wagner3 and Georg Schett1
1 Department of Internal Medicine III, Division of Rheumatology, University of Vienna, Vienna, Austria 2 Institute of Medical Biochemistry, Vienna Biocenter, Vienna, Austria 3 Research Institute of Molecular Pathology, Vienna, Austria 4 Ludwig Boltzmann Institute for Rheumatology, Vienna, Austria 5 Institute of Immunology, Biomedical Science Research Center Alexander Fleming, Vari, Greece
Address correspondence to: Georg Schett, Department of Internal Medicine III, Division of Rheumatology, University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria. Phone: 43-1-40400-4300; Fax: 43-1-40400-4306; E-mail: georg.schett@akh-wien.ac.at.
Received for publication April 1, 2002, and accepted in revised form September 17, 2002.
The detailed cellular and molecular mechanisms leading to joint destruction in rheumatoid arthritis, a disease driven by proinflammatory cytokines, are still unknown. To address the question of whether osteoclasts play a pivotal role in this process, transgenic mice that express human TNF (hTNFtg) and that develop a severe and destructive arthritis were crossed with osteopetrotic, c-fos–deficient mice (c-fos–/–) completely lacking osteoclasts. The resulting mutant mice (c-fos–/–hTNFtg) developed a TNF-dependent arthritis in the absence of osteoclasts. All clinical features of arthritis, such as paw swelling and reduction of grip strength, progressed equally in both groups. Histological evaluation of joint sections revealed no difference in the extent of synovial inflammation, its cellular composition (except for the lack of osteoclasts), and the expression of matrix metalloprotein-ase-3 (MMP-3) and MMP-13. In addition, cartilage damage, proteoglycan loss, and MMP-3, -9, and -13 expression in chondrocytes were similar in hTNFtg and c-fos–/–hTNFtg mice. However, despite the presence of severe inflammatory changes, c-fos–/–hTNFtg mice were fully protected against bone destruction. These data reveal that TNF-dependent bone erosion is mediated by osteoclasts and that the absence of osteoclasts alters TNF-mediated arthritis from a destructive to a nondestructive arthritis. Therefore, in addition to the use of anti-inflammatory therapies, osteoclast inhibition could be beneficial for the treatment of rheumatoid arthritis. |
