The role of vascular cell adhesion molecule 1/ very late activation antigen 4 in endothelial progenitor cell recruitment to rheumatoid arthritis synovium
Version of Record online: 25 MAY 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 6, pages 1817–1826, June 2007
How to Cite
Silverman, M. D., Haas, C. S., Rad, A. M., Arbab, A. S. and Koch, A. E. (2007), The role of vascular cell adhesion molecule 1/ very late activation antigen 4 in endothelial progenitor cell recruitment to rheumatoid arthritis synovium. Arthritis & Rheumatism, 56: 1817–1826. doi: 10.1002/art.22706
- Issue online: 25 MAY 2007
- Version of Record online: 25 MAY 2007
- Manuscript Accepted: 7 MAR 2007
- Manuscript Received: 31 JUL 2006
- NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases institutional training grant. Grant Number: AR-07080
- American Heart Association postdoctoral fellowships. Grant Numbers: 0425749Z, 0625748Z
- American Heart Association postdoctoral fellowship. Grant Number: 0423758Z
- Henry Ford Hospital Foundation. Grant Number: FHFH-A30864
- Veterans Administration Research Services
- NIH. Grant Numbers: AI-40987, HL-58695, AR-48267
- Frederick G. L. Huetwell and William D. Robinson Professorship at the University of Michigan
Marrow-derived endothelial progenitor cells (EPCs) are important in the neovascularization that occurs in diverse conditions such as cardiovascular disorders, inflammatory diseases, and neoplasms. In rheumatoid arthritis (RA), synovial neovascularization propels disease by nourishing the inflamed and hyperproliferative synovium. This study was undertaken to investigate the hypothesis that EPCs selectively home to inflamed joint tissue and may perpetuate synovial neovascularization.
In a collagen-induced arthritis (CIA) model, neovascularization and EPC accumulation in mouse ankle synovium was measured. In an antibody-induced arthritis model, EPC recruitment to inflamed synovium was evaluated. In a chimeric SCID mouse/human synovial tissue (ST) model, mice were engrafted subcutaneously with human ST, and EPC homing to grafts was assessed 2 days later. EPC adhesion to RA fibroblasts and RA ST was evaluated in vitro.
In mice with CIA, cells bearing EPC markers were significantly increased in peripheral blood and accumulated in inflamed synovial pannus. EPCs were 4-fold more numerous in inflamed synovium from mice with anti–type II collagen antibody–induced arthritis versus controls. In SCID mice, EPC homing to RA ST was 3-fold greater than to normal synovium. Antibody neutralization of vascular cell adhesion molecule 1 (VCAM-1) and its ligand component α4 integrin potently inhibited EPC adhesion to RA fibroblasts and RA ST cryosections.
These data demonstrate the selective recruitment of EPCs to inflamed joint tissue. The VCAM-1/very late activation antigen 4 adhesive system critically mediates EPC adhesion to cultured RA fibroblasts and to RA ST cryosections. These findings provide evidence of a possible role of EPCs in the synovial neovascularization that is critical to RA pathogenesis.