Silverman Matthew D, Haas Christian S, Rad Ali M, Arbab Ali S, Koch Alisa E
University of Michigan Health System, Internal Medicine Department, Ann Arbor, MI 48109-2200, USA.
Arthritis Rheum. 2007 Jun;56(6):1817-26. doi: 10.1002/art.22706.
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 alpha4 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.
骨髓来源的内皮祖细胞（EPCs）在多种情况下发生的新血管形成中起重要作用，如心血管疾病、炎症性疾病和肿瘤。在类风湿关节炎（RA）中，滑膜新血管形成为炎症和过度增殖的滑膜提供营养，从而推动疾病进展。本研究旨在探讨EPCs选择性归巢至炎症关节组织并可能使滑膜新血管形成持续存在这一假说。
在胶原诱导的关节炎（CIA）模型中，测量小鼠踝关节滑膜中的新血管形成和EPCs积聚情况。在抗体诱导的关节炎模型中，评估EPCs向炎症滑膜的募集情况。在嵌合SCID小鼠/人滑膜组织（ST）模型中，将人ST皮下植入小鼠体内，2天后评估EPCs向移植物的归巢情况。在体外评估EPCs与RA成纤维细胞和RA ST的黏附情况。
在CIA小鼠中，外周血中携带EPC标志物的细胞显著增加，并积聚在炎症滑膜血管翳中。与对照组相比，抗II型胶原抗体诱导的关节炎小鼠炎症滑膜中的EPCs数量多4倍。在SCID小鼠中，EPCs向RA ST的归巢比向正常滑膜的归巢多3倍。血管细胞黏附分子1（VCAM-1）及其配体α4整合素的抗体中和作用可有效抑制EPCs与RA成纤维细胞和RA ST冰冻切片的黏附。
这些数据表明EPCs选择性募集至炎症关节组织。VCAM-1/极晚期活化抗原4黏附系统关键介导EPCs与培养的RA成纤维细胞和RA ST冰冻切片的黏附。这些发现为EPCs在对RA发病机制至关重要的滑膜新血管形成中可能发挥的作用提供了证据。
