Objective. To assess the ability of pre-B cell colony-enhancing factor (PBEF) to regulate inflammation and degradative processes in inflammatory arthritis, using the small molecule inhibitor APO866 in human fibroblasts in vitro and in murine collageninduced arthritis (CIA).Methods. Enzyme-linked immunosorbent assays were used to examine regulation of expression of metalloproteinases and chemokines in human fibroblasts. The role of PBEF was further examined using APO866 in mice with CIA, with effects on disease activity assessed using radiography, histology, in vivo imaging, and quantitative polymerase chain reaction (qPCR).Results. In vitro activation of human fibroblasts with PBEF promoted expression of matrix metalloproteinase 3 (MMP-3), CCL2, and CXCL8, an effect inhibited by APO866. In mice with CIA, early intervention with APO866 inhibited synovial inflammation, including chemokine-directed leukocyte infiltration, and reduced a systemic marker of inflammation, serum hyaluronic acid. APO866 blockade led to reduced expression of MMP-3 and MMP-13 in joint extracts and to a reduction in a systemic marker of cartilage erosion, serum cartilage oligomeric matrix protein. Radiologic images revealed that APO866 protected against bone erosion, while qPCR demonstrated inhibition of RANKL expression. In mice with established disease, APO866 reduced synovial inflammation and cartilage destruction, and halted bone erosion. In addition, APO866 reduced the activity of MMP-3, CCL2, and RANKL in vivo, and inhibited production of CCL2 and RANKL in synovial explants from arthritic mice, a result that was reversed with nicotinamide mononucleotide.Conclusion. These findings confirm PBEF to be an important regulator of inflammation, cartilage catabolism, and bone erosion, and highlight APO866 as a promising therapeutic agent for targeting PBEF activity in inflammatory arthritis.Pre-B cell colony-enhancing factor (PBEF) represents an inflammatory mediator that exerts enzymatic activities and is highly expressed within the synovial tissue and plasma of patients with rheumatoid arthritis (1,2). In this respect, PBEF acts as a nicotinamide phosphoribosyltransferase (referred to as NAMPT) that controls NAD biosynthesis by catalyzing nicotinamide with 5-phosphoribosyl-1-pyrophosphate (3-5). Conversely, exogenous PBEF is also described as an adipocytokine (referred to as visfatin), and can regulate cellular processes via activation of transcriptional events through NF-B, phosphatidylinositol 3-kinase, and MAP kinase (6-8). Several groups have shown that PBEF interacts with the insulin receptor (8-10); however, this notion remains controversial (11,12), and it may be that PBEF signals through an alternative signaling route. It is also unlikely that this signaling effect is attributable to the endotoxin that may be present in PBEF preparations, since coincubation with polymixin B shows no abrogation of PBEF signaling (6,10,13).In vitro activation of signaling pathways by PBEF has been shown to regulate the expression of metalloproteinases...

NAMPT, also known as pre-B-cell colony-enhancing factor and visfatin, has been proposed to be involved in preventing apoptosis in cancer cells and, as such, has received a great deal of attention in recent years and stimulated the development to specific inhibitors for treating cancer. The role of NAMPT inhibitors as potential therapeutic agents for other diseases has not been studied extensively. Here, we describe their applicability for treating rheumatoid arthritis. We summarize current knowledge of NAMPT expression in healthy and diseased tissues, thereafter, we focus on pathological mechanisms relevant to rheumatoid arthritis that involve the NAMPT pathway and review the current status of NAMPT inhibitors being evaluated in clinical trials.

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