title: TWEAK is a novel arthritogenic mediator.
abstract: 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-1beta (CCL-4), lymphotactin (XCL-1), IFN-gamma-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.
authors.affiliation: Exploratory Sciences, Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Perper
authors.forename: Beth
authors.initials: B
authors.lastname: Browning
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.forename: Shawn
authors.initials: S
authors.lastname: Weng
authors.forename: Cindy
authors.initials: C
authors.lastname: Gao
authors.forename: Keith
authors.initials: K
authors.lastname: Giza
authors.forename: Lihe
authors.initials: L
authors.lastname: Su
authors.forename: Leticia
authors.initials: L
authors.lastname: Tarilonte
authors.forename: Thomas
authors.initials: T
authors.lastname: Crowell
authors.forename: Luis
authors.initials: L
authors.lastname: Rajman
authors.forename: Laura
authors.initials: L
authors.lastname: Runkel
authors.forename: Martin
authors.initials: M
authors.lastname: Scott
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Atkins
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Zheng
authors.forename: Henry
authors.initials: H
authors.lastname: Hess
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001169:Arthritis, Experimental / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D024043:Collagen Type II / Q000008:administration & dosage; D000074049:Cytokine TWEAK; D005620:Freund's Adjuvant / Q000008:administration & dosage; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000502:physiology; D000074050:TWEAK Receptor; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*
chemical_list: D024043:Collagen Type II; D000074049:Cytokine TWEAK; D018836:Inflammation Mediators; D008024:Ligands; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D005620:Freund's Adjuvant