title: Bone Morphogenetic Protein 2 and Transforming Growth Factor β1 Inhibit the Expression of the Proinflammatory Cytokine IL-34 in Rheumatoid Arthritis Synovial Fibroblasts.
abstract: IL-34 is a proinflammatory cytokine implicated in rheumatoid arthritis (RA). The current study aimed to assess the IL-34 expression in response to two members of the transforming growth factor (TGF)-β family, TGF-β1 and bone morphogenetic protein (BMP)-2, in synovial fibroblasts from RA patients. IL-34, TGF-β1, and BMP-2 productions were measured in patient synovial fluids by enzyme-linked immunosorbent assay. IL-34 mRNA levels were quantified by real-time quantitative PCR in human synovial fibroblasts and murine mesenchymal stem cells. Pharmacologic inhibitions were used to determine the involvement of activin receptor-like kinase 1 (ALK1) and ALK5 downstream TGF-β1 and BMP-2. IL-34, TGF-β1, and BMP-2 were expressed in synovial fluids from RA patients. We found a significant correlation between IL-34 and TGF-β1 expressions. Levels of both IL-34 and TGF-β1 were thus correlated with the total leukocyte counts in the synovial fluids. TGF-β1 and BMP-2 decreased IL-34 expression in the synovial fibroblasts or in murine mesenchymal stem cells in a dose- and time-dependent manner through ALK5 and ALK1 pathways, respectively. In addition, TGF-β1 and BMP-2 antagonized tumor necrosis factor α-induced IL-34 gene expression. This work identifies TGF-β1 and BMP-2 as potent inhibitors of IL-34 expression in RA synovial fibroblasts. These cytokines, as upstream inhibitors of IL-34, may thus contribute to antagonize inflammation and bone erosions in RA.
authors.affiliation: French National Cancer League Team 2012, INSERM, UMR 957, Nantes, France; Pathophysiology of Bone Resorption and Primary Bone Tumors Laboratory, Université de Nantes, Nantes, France; Musculoskeletal Department, Nantes University Hospital, Nantes, France.
authors.forename: Marguerite
authors.initials: M
authors.lastname: Chemel
authors.affiliation: French National Cancer League Team 2012, INSERM, UMR 957, Nantes, France; Pathophysiology of Bone Resorption and Primary Bone Tumors Laboratory, Université de Nantes, Nantes, France.
authors.forename: Regis
authors.initials: R
authors.lastname: Brion
authors.affiliation: French National Cancer League Team 2012, INSERM, UMR 957, Nantes, France; Pathophysiology of Bone Resorption and Primary Bone Tumors Laboratory, Université de Nantes, Nantes, France.
authors.forename: Aude-Isabelle
authors.initials: AI
authors.lastname: Segaliny
authors.affiliation: French National Cancer League Team 2012, INSERM, UMR 957, Nantes, France; Pathophysiology of Bone Resorption and Primary Bone Tumors Laboratory, Université de Nantes, Nantes, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Lamora
authors.affiliation: French National Cancer League Team 2012, INSERM, UMR 957, Nantes, France; Pathophysiology of Bone Resorption and Primary Bone Tumors Laboratory, Université de Nantes, Nantes, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Charrier
authors.affiliation: French National Cancer League Team 2012, INSERM, UMR 957, Nantes, France; Pathophysiology of Bone Resorption and Primary Bone Tumors Laboratory, Université de Nantes, Nantes, France.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Brulin
authors.affiliation: Musculoskeletal Department, Nantes University Hospital, Nantes, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Maugars
authors.affiliation: French National Cancer League Team 2012, INSERM, UMR 957, Nantes, France; Pathophysiology of Bone Resorption and Primary Bone Tumors Laboratory, Université de Nantes, Nantes, France; Musculoskeletal Department, Nantes University Hospital, Nantes, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Le Goff
authors.affiliation: French National Cancer League Team 2012, INSERM, UMR 957, Nantes, France; Pathophysiology of Bone Resorption and Primary Bone Tumors Laboratory, Université de Nantes, Nantes, France; Musculoskeletal Department, Nantes University Hospital, Nantes, France; Department of Oncology and Metabolism, INSERM European Associated Laboratory, Sarcoma Research Unit, The Medical School, University of Sheffield, Sheffield, United Kingdom. Electronic address: dominique.heymann@univ-nantes.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: French National Cancer League Team 2012, INSERM, UMR 957, Nantes, France; Pathophysiology of Bone Resorption and Primary Bone Tumors Laboratory, Université de Nantes, Nantes, France. Electronic address: franck.verrecchia@inserm.fr.
authors.forename: Franck
authors.initials: F
authors.lastname: Verrecchia
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D013583:Synovial Membrane / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D055396:Bone Morphogenetic Protein 2; C529076:IL34 protein, human; D007378:Interleukins; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C552364:interleukin-34, mouse; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse