TWEAK is a novel arthritogenic mediator.
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.
Perper
Stuart J
SJ
Exploratory Sciences, Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
Browning
Beth
B
Burkly
Linda C
LC
Weng
Shawn
S
Gao
Cindy
C
Giza
Keith
K
Su
Lihe
L
Tarilonte
Leticia
L
Crowell
Thomas
T
Rajman
Luis
L
Runkel
Laura
L
Scott
Martin
M
Atkins
Gerald J
GJ
Findlay
David M
DM
Zheng
Timothy S
TS
Hess
Henry
H
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*
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