Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

Abstract

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...

Pre-B-cell colony-enhancing factor is markedly elevated in childhood hemophagocytic lymphohistiocytosis

“…The difference between the genetic and acquired forms must also be identified. In recent years, PBEF has been confirmed to be a treatment target for some inflammatory diseases (Evans et al, 2011). The results of this study may lay the foundation for the development of novel PBEF-targeted protocols to inhibit the abnormal inflammatory response in HLH.…”

“…Additionally, PBEF was widely induced by TNF-a, interferon (IFN)-g, IL-1b, IL-6, granulocyte macrophage colony-stimulating factor and other cytokines in neutrophils, monocytes, or macrophages (Jia et al, 2004;Nowell et al, 2006). Inhibition of PBEF significantly decreases the secretion of TNF-a (Evans et al, 2011). PBEF was shown to have an anti-apoptosis effect in macrophages during stress via the signal transducer and activator of transcription 3 survival pathway (Li et al, 2008).…”

Molecular Imaging with Macrophage CRIg-Targeting Nanobodies for Early and Preclinical Diagnosis in a Mouse Model of Rheumatoid Arthritis

“…Molecular imaging with SPECT or PET can greatly complement these techniques by providing information on the presence of specific molecules and cell types in the joints at any one time. Several approaches have already been explored for molecular imaging of RA, including MMPSense or ProSense (24,25), small-molecule probes targeting the folate receptor (26), and antibody-based methods directed against E-Selectin or ICAM-1 (12,27). The key to the success of these approaches is the marker being targeted as well as the specificity and sensitivity of the tracer.…”

PBEF/NAMPT/Visfatin: A Promising Drug Target For Treating Rheumatoid Arthritis?

“…NAMPT expression in the structural cells of the synovial joint NAMPT is expressed (albeit in low levels) in the structural cells within a synovial joint, including in the chondrocytes, synovial fibroblast and macrophage-like cells and adipocytes in Hoffa's fat pad [16,40,74]. This expression is significantly upregulated during synovial inflammation [16,40,74], and both NAMPT mRNA and protein analysis demonstrate that synovial lining fibroblasts and synovial lymphoid aggregates may be the major sources of enhanced NAMPT expression within the synovium [16,40].…”

“…This expression is significantly upregulated during synovial inflammation [16,40,74], and both NAMPT mRNA and protein analysis demonstrate that synovial lining fibroblasts and synovial lymphoid aggregates may be the major sources of enhanced NAMPT expression within the synovium [16,40]. Most strikingly, NAMPT expression has been demonstrated in areas of synovium that are attached to and invading into cartilage and bone [40].…”