Glycation End Products Promote The Osteogenic Differentiation Of Human Endothelial Progenitor Cells Via Sphingosine-l-phosphate Signaling

Backgrounds：Vascular calcification or ectopic mineralization in blood vessels andosteoporosis are important complications in diabetes mellitus. However, they areextremely different: on one hand, vascular bone formation is increased; on the other hand,bone’s bone formation is decreased. It is called the ‘calcification paradox’. However, itsmechanism is unclear. Some important studies we should pay attention to: Firstly, theseearly glycation products undergo further reactions and rearrangements to becomeirreversibly crossed-linked,fluorescent protein derivatives termed advanced glycation endproducts (AGEs). AGE and their receptor RAGE (receptor for AGEs) interaction elicitdiabetic vascular complications.Secondly secreted S1P attracts and acts on osteoblasts toaugment osteoclastogenesis. Taken together, S1P plays an important role inosteoclastogenesis regulation and in communication between osteoclasts andosteoblasts.Thirdly, endothelial progenitor cells (EPCs) are involved in maintainingendothelial homeostasis and contributes to the formation of new blood vessels with aprocess called postnatal vasculogenesis. The mechanisms whereby these cells allow forprotection of the cardiovascular system are still unclear; nevertheless, consistentevidences have shown that impairment and reduction of EPCs are hallmark featuresdiabetes. Therefore, EPC alterations might have a pathogenic role in diabeticcomplications, thus becoming a potential therapeutic target.Objectives: Based on preliminary studies, we mean clear AGEs participate in themolecular mechanisms of diabetic vascular calcification and osteoporosis via S1P.In-depth study will not only help to reveal new mechanisms of diabetes induced vascularcalcification, and will provide new targets for future clinical treatment of drug discoveryand development.Methods and results: AGEs can promote EPCs differentiate towards osteoclastand osteoblast, elevate bone-relevent protein expression in EPCs. Inhibiting RAGEcan’t stop this procession, but inhibiting the expression of S1PR2may down regulate the expression of bone-relevent protein effectively.Conclusion: AGEs can promote EPCs differentiating towards osteoclast andosteoblast, creating “osteoclast-S1P-osteoblast”circle, changing endothelial progenitorcells Self Repairing Systems to osteogenesis system. Inhibiting RAGE can’t stop thisprocession, but S1PR2may be an effective drug target.