title: 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 arthritis.
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 collagen-induced 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Evans
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hayes
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.forename: Mari
authors.initials: M
authors.lastname: Nowell
mesh_terms: D000178:Acrylamides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002356:Cartilage / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000178:Acrylamides; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D054409:Nicotinamide Phosphoribosyltransferase