Mast cell chymase in synovial fluid of collagen-induced-arthritis rats regulates gelatinase release and promotes synovial fibroblasts proliferation via FAK/p21 signaling pathway

Abstract

Mast cells (MCs) were accumulated in synovial tissue of rheumatoid arthritis (RA) patients. MC activation releases numerous mediators including MC-chymase. Synovial fibroblast shows a dramatic hyperplasia in RA articular cavity, but the effects of MC-chymase on synovial fibroblast are unknown. In this study, the collagen-induced-arthritis (CIA) rat model was employed to evaluate the dynamic changes of MC-chymase activity and other inflammatory factors during CIA development in-vivo. The fresh primary synovial fibroblasts from normal or CIA rats were extracted to compare the differences of these two cell-types, and to investigate the effects of MC-chymase on both-types of synovial fibroblast. The data showed that the dynamic changes in chymase activity in synovial fluids of CIA rats before and after immunizations were companied with the changes of tryptase, MMP-2/-9, TNF-α, IL-6, Co-II IgG, total protein, paw-thickness and body weight in-vivo. The baseline differences in cell grow rates, expression levels of p21, FAK, MMP-9 between normal and CIA-SFB have been seen. Compared to the normal synovial fibroblasts, CIA-SFB increased the percentage of the cells transferred to S or G2/M phases in cell cycle in-vivo; CIA-SFB become more proliferative with high-expression MMP-2/9 during CIA development. MC-chymase in-vitro promoted both types of synovial fibroblast proliferation and induced cell cycle changes, but CIA-synovial fibroblasts exhibited much stronger responses to MC-chymase stimulation by increased expression levels of p21, FAK, MMP-9 which associated with cell adhesion and migration. This study might give a new insight that the activated mast cell can be an important target cell for RA treatment and suggest that MC-chymase needs well attention for therapeutic aims.