Sphingosine kinase 1/sphingosine 1-phosphate/sphingosine 1-phosphate receptor 1 pathway: A novel target of geniposide to inhibit angiogenesis

Objective: Rheumatoid arthritis (RA) is a common inflammatory autoimmune disease characterized by the formation of joint synovitis and pannus. Sphingosine 1-phosphate (S1P) is an important mediator related to angiogenesis, inflammation and autoimmunity. As Geniposide (GE) has potent immuno-modulation function, we investigated the effects on the dynamic balance of angiogenesis-related factors and Sphingosine kinase 1 (SphK1)-S1P-S1P receptor 1 (S1PR1) signal transduction in adjuvant-induced arthritis (AA) rats. Method: The model evaluation was performed from paw swelling degree, arthritis index and movement score. The immunohistochemistry and enzyme-linked immunosorbent assay were used to study the microvascular density (MVD) and pro/anti-angiogenic factors levels. The cell viability was examined by cell counting kit-8 assay. SphK1, S1PR1 mRNA and protein levels in fibroblast-like synoviocytes (FLSs) were detected by quantitative real-time polymerase chain reaction and Western blotting. Results: The results showed that GE can apparently suppressed the inflammatory pathological status. The arthritis index, paw swelling and MVD of AA rats were decreased with dose dependence (*P < 0.05, **P < 0.01). In addition, GE can reduce the secretion of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), promote the secretion of endostatin (ES) and inhibit excessive proliferation of FLSs (*P < 0.05, **P < 0.01). Importantly, GE can significantly inhibit the activity of SphK1, the level of S1P and the expression of SphK1 and S1PR1 in FLSs (*P < 0.05, **P < 0.01). Conclusion: It indicated that GE reduces the activity of SphK1 by restoring the dynamic balance between pro/anti-angiogenic factors, thereby interfering with SphK1-S1P-S1PR1 signal transduction, reducing the formation of synovial microvessels and exerting anti-angiogenesis effect of RA.