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.
Highlights
Rheumatoid arthritis (RA) is characterized by synovial inflammation and bone erosion[1,2]
To elucidate potential mechanisms by which the induction of arthritis is suppressed in Nampt+/− mice, we measured the serum levels of the arthritogenic anti-mouse CII auto-antibody, which plays a crucial role in the initiation of CIA7
To validate the RNA-seq results functionally and to initiate signal transduction analyses of Nampt mediated pathways in Collageninduced arthritis (CIA) Nampt+/− mice, we focused on GM26870, a differentially expressed long non-coding RNA, to examine whether it may be a component underlying the Relative Fold Change Relative Fold Change Relative Fold Change
Summary
Rheumatoid arthritis (RA) is characterized by synovial inflammation and bone erosion[1,2]. Current therapies for arthritis are inadequate and there remains a need for additional therapeutic targets. Nicotinamide phosphoribosyltransferase (NAMPT) is an essential gene[3] which functions in NAD synthesis, apoptosis, and inflammation[4]. NAMPT is expressed in most organs, tissues, and cells examined[4]. Because of its pleiotropic functions, dysregulated NAMPT expression. Nampt in arthritis in well-established Nampt knockdown (Nampt+/−) and Nampt overexpression (NamptOE) mice to substantiate that Nampt is a genetic risk factor and potential therapeutic target in RA. This study investigated the molecular mechanisms of
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