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Am J Pathol. 2017 Jan;187(1):156-162. doi: 10.1016/j.ajpath.2016.09.015. Epub 2016 Nov 17.

Bone Morphogenetic Protein 2 and Transforming Growth Factor β1 Inhibit the Expression of the Proinflammatory Cytokine IL-34 in Rheumatoid Arthritis Synovial Fibroblasts.

Author information

1
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.
2
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.
3
Musculoskeletal Department, Nantes University Hospital, Nantes, France.
4
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.
5
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.

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.

PMID:
27865758
DOI:
10.1016/j.ajpath.2016.09.015
[Indexed for MEDLINE]
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