title: TWEAK promotes osteoclastogenesis in rheumatoid arthritis.
abstract: Bone destruction is critical in the functional disability of patients with rheumatoid arthritis (RA). Osteoclasts, specialized bone-resorbing cells regulated by cytokines, such as receptor activator of NF-κB ligand (RANKL), are primarily implicated in bone destruction in RA. The aim of the study was to examine whether tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, has osteoclastogenic activity in patients with RA and in animal models, including mice with collagen-induced arthritis (CIA) and IL-1 receptor antagonist knockout (IL-1RaKO) mice. TWEAK was increased in the synovium, synovial fluid, and serum of patients with RA and in the synovium of CIA mice and IL-1RaKO mice. TWEAK induced RANKL expression in mixed joint cells and splenocytes from CIA mice, IL-1RaKO mice, and fibroblast-like synoviocytes from patients with RA. Both osteoclast precursor cells and osteoclasts express TWEAK receptor fibroblast growth factor-inducible 14. In addition, TWEAK enhanced in vitro osteoclastogenesis without the presence of RANKL-providing cells and by inducing RANKL expression in fibroblast-like synoviocytes. Moreover, treatment with fibroblast growth factor-inducible 14-Fc inhibited RANKL-induced osteoclastogenesis, indicating that endogenous TWEAK also has osteoclastogenic activity. Our data demonstrated that TWEAK promotes osteoclastogenesis in RA, suggesting that therapeutic strategies targeting TWEAK could be effective for treatment of patients with RA, especially in preventing bone destruction.
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Jin-Sil
authors.initials: JS
authors.lastname: Park
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kwok
authors.forename: Mi-Ae
authors.initials: MA
authors.lastname: Lim
authors.forename: Hye-Joa
authors.initials: HJ
authors.lastname: Oh
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Jhun
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Ju
authors.forename: Kyung-Su
authors.initials: KS
authors.lastname: Park
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Park
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Young-Gyu
authors.initials: YG
authors.lastname: Cho
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007596:Joints / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects; D053245:RANK Ligand / Q000378:metabolism / Q000494:pharmacology; D013154:Spleen / Q000473:pathology; D013582:Synovial Fluid / Q000187:drug effects / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D000074049:Cytokine TWEAK; D053245:RANK Ligand; C109743:TNFSF12 protein, human; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D016173:Macrophage Colony-Stimulating Factor