title: TWEAK/Fn14 interaction regulates RANTES production, BMP-2-induced differentiation, and RANKL expression in mouse osteoblastic MC3T3-E1 cells.
abstract: Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a member of the TNF family, is a multifunctional cytokine that regulates cell growth, migration, and survival principally through a TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14). However, its physiological roles in bone are largely unknown. We herein report various effects of TWEAK on mouse osteoblastic MC3T3-E1 cells. MC3T3-E1 cells expressed Fn14 and produced RANTES (regulated upon activation, healthy T cell expressed and secreted) upon TWEAK stimulation through PI3K-Akt, but not nuclear factor-kappaB (NF-kappaB), pathway. In addition, TWEAK inhibited bone morphogenetic protein (BMP)-2-induced expression of osteoblast differentiation markers such as alkaline phosphatase through mitogen-activated protein kinase (MAPK) Erk pathway. Furthermore, TWEAK upregulated RANKL (receptor activation of NF-kappaB ligand) expression through MAPK Erk pathway in MC3T3-E1 cells. All these effects of TWEAK on MC3T3-E1 cells were abolished by mouse Fn14-Fc chimera. We also found significant TWEAK mRNA or protein expression in osteoblast- and osteoclast-lineage cell lines or the mouse bone tissue, respectively. Finally, we showed that human osteoblasts expressed Fn14 and induced RANTES and RANKL upon TWEAK stimulation. Collectively, TWEAK/Fn14 interaction regulates RANTES production, BMP-2-induced differentiation, and RANKL expression in MC3T3-E1 cells. TWEAK may thus be a novel cytokine that regulates several aspects of osteoblast function.
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ando
authors.forename: Jiro
authors.initials: J
authors.lastname: Ichikawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Wako
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Hatsushika
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Michitomo
authors.initials: M
authors.lastname: Sakuma
authors.forename: Kachio
authors.initials: K
authors.lastname: Tasaka
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hamada
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Nakao
mesh_terms: D016475:3T3 Cells; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D018946:Chemokine CCL5 / Q000378:metabolism*; D002678:Chimera; D000074049:Cytokine TWEAK; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000074050:TWEAK Receptor; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D018946:Chemokine CCL5; D000074049:Cytokine TWEAK; D053245:RANK Ligand; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C000613297:TNFRSF12A protein, human; C505688:TNFSF11 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C505689:Tnfsf11 protein, mouse; C491645:Tnfsf12 protein, mouse; D016212:Transforming Growth Factor beta; D048069:Tumor Necrosis Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt