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Epigenetic regulation of NfatC1 transcription and osteoclastogenesis by nicotinamide phosphoribosyl transferase in the pathogenesis of arthritis

ABSTRACT: Nicotinamide phosphoribosyltransferase (NAMPT) functions in NAD synthesis, apoptosis, and inflammation. Dysregulation of NAMPT has been associated with several inflammatory diseases, including rheumatoid arthritis (RA). The purpose of this study was to investigate NAMPT’s role in arthritis using mouse and cellular models. Collagen-induced arthritis (CIA) in DBA/1J Nampt+/- mice was evaluated by ELISA, micro-CT and RNA-sequencing (RNA-seq). In vitro Nampt loss-of-function and gain-of-function studies on osteoclastogenesis were examined by TRAP staining, nascent RNA capture, luciferase reporter assays, and ChIP-PCR. Nampt-deficient mice presented with suppressed inflammatory bone destruction and disease progression in a CIA mouse model. Nampt expression was required for the epigenetic regulation of the Nfatc1 promoter and osteoclastogenesis. Finally, RNA-seq identified 690 differentially expressed genes in whole ankle joints which associated (P<0.05) with Nampt expression and CIA. Selected target was validated by RT-PCR or functional characterization. We have provided evidence that NAMPT functions as a genetic risk factor and a potential therapeutic target to RA.

ORGANISM(S): Mus musculus

PROVIDER: GSE121793 | GEO | 2019/01/31

REPOSITORIES: GEO

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Project description:The pathogenesis of rheumatoid arthritis (RA) is complicated and involves both innate and adaptive immunity [5]. The innate immunity such as macrophages or fibroblast-like synoviocytes (FLS) in the synovium can generate inflammatory mediators, including TNF-α, IL-1, IL-6, IL-17, IFN-γ, and chemo kines that lead to synovial inflammation, bone erosion, and cartilage damage [6-8]. The IL-17 signaling mediates the autoantibody production in collagen-induced arthritis (CIA) model [9]. However, the treatment response with an anti-IL17 monoclonal antibody in RA patients shows a high degree of heterogeneity [10]. The inhibitors of the Janus kinase (JAK) pathway are approved for RA patients [11]. These data suggest that the targeted multiple cytokines through the JAK pathway are useful for RA treatment. Disturbance of type I IFNs (IFNs-I) signaling and production drive autoimmune development [12]. The presymptomatic RA patients display an increase of IFNs-I before the onset of symptoms [13]. The RA patients also show the elevation of IFN- α in the synovial fluid and high expression of IFNs-I regulated gene in peripheral blood mononuclear cells (PBMC) [14]. However, the role of IFNs-I in arthritis and bone homeostasis has suggested the accelerating effect of arthritis and bone damage. The interferon-alpha receptor knockout mice develop arthritis severity higher than wild-type mice in the model of antigen-induced arthritis [15]. IFNs-I also affects the bone homeostasis by inhibiting osteoclastogenesis via receptor activator of nuclear factor-kappa B (RANK) pathway, and reduction of c-FOS expression [16-18]. Therefore, the goal of RA treatment with antagonizing the IFNs-I pathway has to be optimized between efficacy and potentially adverse effect. STING is a cytosolic DNA sensor that initiates the production of IFNs-I. STING functions have been reported as both pro-inflammatory signaling and negative regulator against inflammation [19-21]. The mutation in exon 5 of the STING gene results in gain function leading to initiate inflammation and cause the Sting associated vasculopathy with onset in infancy (SAVI) [22]. Loss of STING function rescues DNaseII-deficient mice from lethality and polyarthritis [23]. However, Sting-deficient lupus mice (MRL/Lpr mice) show higher and earlier mortality than Sting-sufficient MRL/Lpr mice [24]. The pathology also shows lymphoid hypertrophy with a higher amount of macrophages and granulocytes infiltration, autoantibodies, and cytokine [24]. The objective of this study was to identify the role of STING in the pathogenesis of rheumatoid arthritis using collagen-induced arthritis (CIA) model as a representative model of the human RA.

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Epigenetic regulation of NfatC1 transcription and osteoclastogenesis by nicotinamide phosphoribosyl transferase in the pathogenesis of arthritis

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