Journal
CELLS
Volume 10, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/cells10082168
Keywords
S1P (sphingosine-1-phosphate); vascular endothelial growth factor; osteoblasts; rheumatoid arthritis
Categories
Funding
- Ministry of Science and Technology in Taiwan [MOST 108-2314-B-039-034-MY3, MOST 108-2320-B-039-057, MOST 108-2320-B-039-065, MOST 110-2320-B-039-022-MY3]
- China Medical University Hospital [DMR-110-022]
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Angiogenesis and S1P play crucial roles in the pathogenesis of RA, with S1P treatment promoting VEGF production and angiogenesis. Infection with SphK1 shRNA can reduce angiogenesis and joint swelling, indicating the therapeutic potential of S1P in RA treatment.
Angiogenesis is a critical process in the formation of new capillaries and a key participant in rheumatoid arthritis (RA) pathogenesis. Vascular endothelial growth factor (VEGF) stimulation of endothelial progenitor cells (EPCs) facilitates angiogenesis and the progression of RA. Phosphorylation of sphingosine kinase 1 (SphK1) produces sphingosine-1-phosphate (S1P), which increases inflammatory cytokine production, although the role of S1P in RA angiogenesis is unclear. In this study, we evaluated the impact of S1P treatment on VEGF-dependent angiogenesis in osteoblast-like cells (MG-63 cells) and the significance of SphK1 short hairpin RNA (shRNA) on S1P production in an in vivo model. We found significantly higher levels of S1P and VEGF expression in synovial fluid from RA patients compared with those with osteoarthritis by ELISA analysis. Treating MG-63 cells with S1P increased VEGF production, while focal adhesion kinase (FAK) and Src siRNAs and inhibitors decreased VEGF production in S1P-treated MG-63 cells. Conditioned medium from S1P-treated osteoblasts significantly increased EPC tube formation and migration by inhibiting miR-16-5p synthesis via proto-oncogene tyrosine-protein kinase src (c-Src) and FAK signaling in chick chorioallantoic membrane (CAM) and Matrigel plug assays. Infection with SphK1 shRNA reduced angiogenesis, articular swelling and cartilage erosion in the ankle joints of mice with collagen-induced arthritis (CIA). S1P appears to have therapeutic potential in RA treatment.
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