Rheumatoid Arthritis Basic Science Studies
Pre–B cell colony-enhancing factor/visfatin, a new marker of inflammation in rheumatoid arthritis with proinflammatory and matrix-degrading activities
Article first published online: 30 AUG 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 9, pages 2829–2839, September 2007
How to Cite
Brentano, F., Schorr, O., Ospelt, C., Stanczyk, J., Gay, R. E., Gay, S. and Kyburz, D. (2007), Pre–B cell colony-enhancing factor/visfatin, a new marker of inflammation in rheumatoid arthritis with proinflammatory and matrix-degrading activities. Arthritis & Rheumatism, 56: 2829–2839. doi: 10.1002/art.22833
- Issue published online: 30 AUG 2007
- Article first published online: 30 AUG 2007
- Manuscript Accepted: 17 MAY 2007
- Manuscript Received: 15 FEB 2007
- Swiss National Fund. Grant Number: 3200B0-105923
- Fund for Medical Research of the University of Zurich
To study possible mechanisms that mediate induction of the recently described adipocytokine pre–B cell colony-enhancing factor (PBEF) in joints of patients with rheumatoid arthritis (RA), and to analyze whether levels of PBEF correlate with disease severity and whether PBEF itself has the potential to act as a proinflammatory and destructive mediator in RA.
RA synovial fibroblasts (RASFs) and monocytes were stimulated with Toll-like receptor (TLR) ligands, cytokines, and recombinant human PBEF or were transfected with PBEF expression constructs or with PBEF-specific small interfering RNA. Production of interleukin-6 (IL-6), IL-8, and tumor necrosis factor α (TNFα) was measured by enzyme-linked immunosorbent assay, and expression of matrix metalloproteinases (MMPs) was assessed by real-time polymerase chain reaction. PBEF expression in synovial tissue, synovial fluid, serum, and SFs was assessed by immunohistochemistry, in situ hybridization, Western blotting, and enzyme immunoassays.
In RASFs, PBEF was up-regulated by TLR ligands and cytokines that are characteristically present in the joints of patients with RA. In synovial tissue, RASFs were the major PBEF-expressing cells. A predominance of PBEF was found in the synovial lining layer and at sites of invasion into cartilage. Levels of PBEF in serum and synovial fluid correlated with the degree of inflammation and clinical disease activity. Moreover, PBEF itself activated the transcription factors NF-kB and activator protein 1 and induced IL-6, IL-8, MMP-1, and MMP-3 in RASFs as well as IL-6 and TNFα in monocytes. PBEF knockdown in RASFs significantly inhibited basal and TLR ligand–induced production of IL-6, IL-8, MMP-1, and MMP-3.
Our findings establish PBEF as a proinflammatory and destructive mediator of joint inflammation in RA and identify PBEF as a potential therapeutic target.