HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Perper, S. J. Articles by Hess, H. Search for Related Content PubMed PubMed Citation Articles by Perper, S. J. Articles by Hess, H.

TWEAK Is a Novel Arthritogenic Mediator

Stuart J. Perper^*, Beth Browning^*, Linda C. Burkly^*, Shawn Weng^*, Cindy Gao^*, Keith Giza^*, Lihe Su^*, Leticia Tarilonte^*, Thomas Crowell^*, Luis Rajman^*, Laura Runkel^*, Martin Scott^*, Gerald J. Atkins, David M. Findlay, Timothy S. Zheng^1,2,* and Henry Hess^1,*

^* Biogen Idec, Cambridge, MA 02142; and Department of Orthopaedics and Trauma, University of Adelaide, Adelaide, Australia

TNF-like weak inducer of apoptosis (TWEAK) is a TNF family member with pleiotropic effects on a variety of cell types, one of which is the induction of proinflammatory cytokines by synovial fibroblasts derived from rheumatoid arthritis (RA) patients. In this study, we report that the serum TWEAK level was dramatically elevated during mouse collagen-induced arthritis (CIA) and blocking TWEAK by a neutralizing mAb significantly reduced the clinical severity of CIA. Histological analyses also revealed that TWEAK inhibition diminished joint inflammation, synovial angiogenesis, as well as cartilage and bone erosion. Anti-TWEAK treatment proved efficacious when administered just before the disease onset but not during the priming phase of CIA. Consistent with this, TWEAK inhibition did not affect either cellular or humoral responses to collagen. In contrast, TWEAK inhibition significantly reduced serum levels of a panel of arthritogenic mediators, including chemokines such as MIP-1 (CCL-4), lymphotactin (XCL-1), IFN--inducible protein 10 (IP-10) (CXCL-10), MCP-1 (CCL-2), and RANTES (CCL-5), as well as the matrix metalloprotease-9. Exploring the possible role of the TWEAK/Fn14 pathway in human RA pathogenesis, we showed that TWEAK can target human primary chondrocytes and osteoblast-like cells, in addition to synovial fibroblasts. We further demonstrated that TWEAK induced the production of matrix metalloproteases in human chondrocytes and potently inhibited chondrogenesis and osteogenesis using in vitro models. These results provide evidence for a novel cytokine pathway that contributes to joint tissue inflammation, angiogenesis, and damage, as well as may inhibit endogenous repair, suggesting that TWEAK may be a new therapeutic target for human RA.

This article has been cited by other articles:

				G. Tiller, P. Fischer-Posovszky, H. Laumen, A. Finck, T. Skurk, M. Keuper, U. Brinkmann, M. Wabitsch, D. Link, and H. Hauner Effects of TWEAK (TNF Superfamily Member 12) on Differentiation, Metabolism, and Secretory Function of Human Primary Preadipocytes and Adipocytes Endocrinology, December 1, 2009; 150(12): 5373 - 5383. [Abstract] [Full Text] [PDF]

				K. Schapira, L. C. Burkly, T. S. Zheng, P. Wu, M. Groeneweg, M. Rousch, M. M. Kockx, M. J.A.P. Daemen, and S. Heeneman Fn14-Fc Fusion Protein Regulates Atherosclerosis in ApoE-/- Mice and Inhibits Macrophage Lipid Uptake In Vitro Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 2021 - 2027. [Abstract] [Full Text] [PDF]

				K. YANABA, A. YOSHIZAKI, E. MUROI, T. HARA, F. OGAWA, A. USUI, M. HASEGAWA, M. FUJIMOTO, K. TAKEHARA, and S. SATO Elevated Circulating TWEAK Levels in Systemic Sclerosis: Association with Lower Frequency of Pulmonary Fibrosis J Rheumatol, August 1, 2009; 36(8): 1657 - 1662. [Abstract] [Full Text] [PDF]

				M. Kumar, D. Y. Makonchuk, H. Li, A. Mittal, and A. Kumar TNF-Like Weak Inducer of Apoptosis (TWEAK) Activates Proinflammatory Signaling Pathways and Gene Expression through the Activation of TGF-{beta}-Activated Kinase 1 J. Immunol., February 15, 2009; 182(4): 2439 - 2448. [Abstract] [Full Text] [PDF]

				M. Razmara, B. Hilliard, A. K. Ziarani, R. Murali, S. Yellayi, M. Ghazanfar, Y. H. Chen, and M. L. Tykocinski Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis Am. J. Pathol., February 1, 2009; 174(2): 460 - 474. [Abstract] [Full Text] [PDF]

				T. S. Zheng and L. C. Burkly No end in site: TWEAK/Fn14 activation and autoimmunity associated- end-organ pathologies J. Leukoc. Biol., August 1, 2008; 84(2): 338 - 347. [Abstract] [Full Text] [PDF]

				S. Kamijo, A. Nakajima, K. Kamata, H. Kurosawa, H. Yagita, and K. Okumura Involvement of TWEAK/Fn14 interaction in the synovial inflammation of RA Rheumatology, April 1, 2008; 47(4): 442 - 450. [Abstract] [Full Text] [PDF]

				Z. Zhao, L. C. Burkly, S. Campbell, N. Schwartz, A. Molano, A. Choudhury, R. A. Eisenberg, J. S. Michaelson, and C. Putterman TWEAK/Fn14 Interactions Are Instrumental in the Pathogenesis of Nephritis in the Chronic Graft-versus-Host Model of Systemic Lupus erythematosus J. Immunol., December 1, 2007; 179(11): 7949 - 7958. [Abstract] [Full Text] [PDF]

				L. C. Bover, M. Cardo-Vila, A. Kuniyasu, J. Sun, R. Rangel, M. Takeya, B. B. Aggarwal, W. Arap, and R. Pasqualini A Previously Unrecognized Protein-Protein Interaction between TWEAK and CD163: Potential Biological Implications J. Immunol., June 15, 2007; 178(12): 8183 - 8194. [Abstract] [Full Text] [PDF]

				C. Dogra, H. Changotra, N. Wedhas, X. Qin, J. E. Wergedal, and A. Kumar TNF-related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle-wasting cytokine FASEB J, June 1, 2007; 21(8): 1857 - 1869. [Abstract] [Full Text] [PDF]