Plasma kallikrein-kinin system activation regulates the synovial recruitment of endothelial progenitor cells in arthritis

Objective: To examine whether the activation of plasma kallikrein-kinin system(KKS) regulates synovial recruitment of endothelial progenitor cells(EPCs) in arthritis.Methods: EPCs were isolated from bone marrow of Lewis rats and identified by RT-PCR.Inflammatory arthritis in Lewis rats was induced by intraperitoneal injection of peptidoglycan-polysaccharide(PG-PS).Recruitment of EPCs in inflamed synovium were evaluated by tail vein injection of EPCs.The role of KKS was examined using a specific inhibitor of plasma kallikrein,EPI-KAL2,the effects were evaluated by measuring the change of joint diameter and mumber of recruitment EPCs.Results: Bone marrow-derived rat EPCs express endothelial cell marker mRNA such as CD144,CD31,vWF,and exclusively expressed hematopoietic progenitor cell markers,Sca-1.In Lewis rats bearing arthritis,EPCs were recruited into inflamed synovium at acute phase.Plasma kallikrein inhibitor EPI-KAL2 significantly suppressed the synovial recruitment of EPCs as well as the joint swelling.Conclusion: Plasma KKS activation mediates EPC homing to inflamed synovium.These observations demonstrate a novel role for plasma KKS activation in arthritis.