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.