Monocyte chemoattractant protein­1 promotes the proliferation, migration and differentiation potential of fibroblast­like synoviocytes via the PI3K/P38 cellular signaling pathway.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints and joint destruction. Monocyte chemoattractant protein 1 (MCP­1) is highly expressed in the joints of patients suffering from RA. The present study aimed to evaluate the effects of MCP­1 on the phenotype of fibroblast­like synoviocytes (FLSs) and their differentiation potential towards vascular endothelial cells. The expression of MCP­1 in collagen­induced arthritis (CIA) rats was investigated by PCR, ELISA and immunohistology. Cell proliferation induced by MCP­1 was measured using a Cell Counting Kit­8 (CCK­8) and 5­Bromo­2­deoxyuridine ELISA assay. In addition, the effects of MCP­1 on the migration of FLSs was examined using a Transwell assay. Activation of PI3K and P38 were investigated by western blotting following MCP­1 treatment. The vascular endothelial cell markers, tumor necrosis factor alpha (TNF­α) and interleukin­1 beta (IL­ß), were also examined by western blotting. LY294002 [PI3K inhibitor, (LY)] and SB203580 [P38 inhibitor, (SB)] were used to examine the proliferative and pro­differentiation effect of PI3K and P38. The present findings showed that the expression level of MCP­1 in the synovium of CIA rats was significantly higher compared with controls. The present in vitro study suggested that MCP­1 increased the FLSs cell numbers with a maximal effect at 200 ng/ml, and induced the maximal phosphorylation of PI3K at 15 min and P38 at 30 min. In addition, MCP­1 stimulation significantly increased the migration of FLSs. Furthermore, MCP­1­induced the expression of vascular endothelial growth factor and CD31 in FLSs. Suppression of PI3K and P38 was found to reduce MCP­1 induced FLSs proliferation and migration, and decreased the expression levels of angiogenesis markers increased following MCP­1 treatment. MCP­1 was also found to increase the expression levels of both TNF­α and IL­ß. Therefore, MCP­1 could promote the proliferation and migration of FLSs, and was found to increase the expression levels of various angiogenesis markers via PI3K/P38, suggesting a role for this pathway in synovium hyperplasia in RA.