PMID- 21400478
OWN - NLM
STAT- MEDLINE
DCOM- 20110901
LR  - 20220129
IS  - 1529-0131 (Electronic)
IS  - 0004-3591 (Linking)
VI  - 63
IP  - 7
DP  - 2011 Jul
TI  - 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.
PG  - 1866-77
LID - 10.1002/art.30338 [doi]
AB  - 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. 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.
CI  - Copyright (c) 2011 by the American College of Rheumatology.
FAU - Evans, Laura
AU  - Evans L
AD  - Cardiff University School of Medicine, Cardiff, UK.
FAU - Williams, Anwen S
AU  - Williams AS
FAU - Hayes, Anthony J
AU  - Hayes AJ
FAU - Jones, Simon A
AU  - Jones SA
FAU - Nowell, Mari
AU  - Nowell M
LA  - eng
GR  - 17654/ARC_/Arthritis Research UK/United Kingdom
GR  - 17654/VAC_/Versus Arthritis/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Acrylamides)
RN  - 0 (N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide)
RN  - 0 (Piperidines)
RN  - EC 2.4.2.12 (Nicotinamide Phosphoribosyltransferase)
SB  - IM
MH  - Acrylamides/pharmacology/*therapeutic use
MH  - Animals
MH  - Arthritis, Experimental/*drug therapy/metabolism/pathology
MH  - Cartilage/*metabolism/pathology
MH  - Fibroblasts/metabolism/pathology
MH  - Humans
MH  - Inflammation/metabolism/pathology
MH  - Leukocytes/*drug effects/metabolism/pathology
MH  - Mice
MH  - Nicotinamide Phosphoribosyltransferase/*antagonists & inhibitors
MH  - Piperidines/pharmacology/*therapeutic use
EDAT- 2011/03/15 06:00
MHDA- 2011/09/02 06:00
CRDT- 2011/03/15 06:00
PHST- 2011/03/15 06:00 [entrez]
PHST- 2011/03/15 06:00 [pubmed]
PHST- 2011/09/02 06:00 [medline]
AID - 10.1002/art.30338 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2011 Jul;63(7):1866-77. doi: 10.1002/art.30338.