title: Macrophage migration inhibitory factor is essential for osteoclastogenic mechanisms in vitro and in vivo mouse model of arthritis.
abstract: Macrophage migration inhibitory factor (MIF) enhances activation of leukocytes, endothelial cells and fibroblast-like synoviocytes (FLS), thereby contributing to the pathogenesis of rheumatoid arthritis (RA). A MIF promoter polymorphism in RA patients resulted in higher serum MIF concentration and worsens bone erosion; controversially current literature reported an inhibitory role of MIF in osteoclast formation. The controversial suggested that the precise role of MIF and its putative receptor CD74 in osteoclastogenesis and RA bone erosion, mediated by locally formed osteoclasts in response to receptor activator of NF-κB ligand (RANKL), is unclear. We reported that in an in vivo K/BxN serum transfer arthritis, reduced clinical and histological arthritis in MIF(-/-) and CD74(-/-) mice were accompanied by a virtual absence of osteoclasts at the synovium-bone interface and reduced osteoclast-related gene expression. Furthermore, in vitro osteoclast formation and osteoclast-related gene expression were significantly reduced in MIF(-/-) cells via decreasing RANKL-induced phosphorylation of NF-κB-p65 and ERK1/2. This was supported by a similar reduction of osteoclastogenesis observed in CD74(-/-) cells. Furthermore, a MIF blockade reduced RANKL-induced osteoclastogenesis via deregulating RANKL-mediated NF-κB and NFATc1 transcription factor activation. These data indicate that MIF and CD74 facilitate RANKL-induced osteoclastogenesis, and suggest that MIF contributes directly to bone erosion, as well as inflammation, in RA.
authors: Centre for Inflammatory Disease, Monash University, Clayton, Australia.
authors: Ran
authors: R
authors: Gu
authors: Centre for Inflammatory Disease, Monash University, Clayton, Australia.
authors: Leilani L
authors: LL
authors: Santos
authors: Centre for Inflammatory Disease, Monash University, Clayton, Australia.
authors: Devi
authors: D
authors: Ngo
authors: Centre for Inflammatory Disease, Monash University, Clayton, Australia.
authors: HuaPeng
authors: H
authors: Fan
authors: Prince Henry's Institute, Clayton, Australia.
authors: Preetinder P
authors: PP
authors: Singh
authors: University Hospital Cologne, Cologne, Germany.
authors: Gunter
authors: G
authors: Fingerle-Rowson
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
authors: Richard
authors: R
authors: Bucala
authors: School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Australia.
authors: Jiake
authors: J
authors: Xu
authors: Prince Henry's Institute, Clayton, Australia; Dept of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
authors: Julian M W
authors: JM
authors: Quinn
authors: Centre for Inflammatory Disease, Monash University, Clayton, Australia. Electronic address: eric.morand@monash.edu.
authors: Eric F
authors: EF
authors: Morand
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D001862:Bone Resorption; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000949:Histocompatibility Antigens Class II / Q000502:physiology; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency* / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000502:physiology; D010010:Osteoclasts / Q000502:physiology*; D053245:RANK Ligand / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C045084:invariant chain
keywords: Bone; Cell signals; Cytokines; Inflammation; Transcription factors
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