Sorafenib suppresses proliferation rate of fibroblast-like synoviocytes through the arrest of cell cycle in experimental adjuvant arthritis

Objectives: Rheumatoid arthritis, a recurrent incendiary autoimmune joint syndrome, features by prominent synovial hyperplasia. Fibroblast-like synoviocytes are the executive components in the pathogenesis of rheumatoid arthritis. It is generally accepted that excessive proliferation and reduced apoptosis of fibroblast-like synoviocytes lead to synovial hyperplasia. Our previously studies found that sorafenib could inhibit adjuvant arthritis in rats and induced adjuvant arthritis fibroblast-like synoviocytes apoptosis. Presently, we aim to investigate the inhibitory effect with mechanisms of action of sorafenib on adjuvant arthritis fibroblast-like synoviocytes proliferation. Methods: Cell counting kit-8 and flow cytometry detection were conducted to monitor FLSs proliferation and cell cycle. Western blotting and qPCR assays were performed to detect P21, P53, CDK4, CyclinD1 and proliferating cell nuclear antigen content levels. Key findings: Sorafenib significantly inhibited adjuvant arthritis fibroblast-like synoviocytes proliferation with an IC50 value of 4 μmol/L by a concentration-dependent pattern, which accompanies by G1 cell cycle arrest. Also, sorafenib significantly decreased the levels of P21, CyclinD1, CDK4 and proliferating cell nuclear antigen, as well as up-regulated P53 expression in adjuvant arthritis fibroblast-like synoviocytes. Conclusions: Sorafenib could inhibit adjuvant arthritis fibroblast-like synoviocytes proliferation via arresting G1/S cell cycle progression, which was partially through CDK4/CyclinD1-mediated pathway, as well as up-regulating P53 and down-regulating proliferating cell nuclear antigen expressions. These results suggest that sorafenib may provide a new paradigm for rheumatoid arthritis treatment.