Studies Of The Changes And Roles Of Glycometabolism In Osteogenic Differentiation Of MSCs Under Simulated Microgravity Conditions

Bone marrow mesenchymal stem cells(BMSCs)are multipotent stromal cells that derived from bone marrow and are the major source of osteoblasts.Bone loss is the phenomenon that astronauts face during spaceflight,which is considered to be related to the inhibition of osteogenic differentiation of BMSCs under microgravity conditions.Although it has been reported that microgravity could inhibit the osteogenic differentiation of BMSCs,the molecular mechanism underlying how microgravity affects the osteogenesis of BMSCs is not fully understood.Glycometabolism is the key content of cell metabolism and plays an important role in maintaining cellular functions.The alterations of glycometabolism will affect the cellular behaviors.Studies have shown that the energy for BMSCs to sustain its proliferation and stemness are usually derived from glycolysis.However,oxidative phosphorylation(OXPHOS)becomes the main way to produce energy for differentiation of BMSCs.At present,it has not been reported that the changes and roles of cellular glycometabolism in microgravity-inhibited osteogenic differentiation of BMSCs.Therefore,this study explored the molecular mechanism of microgravity affected osteogenic differentiation of BMSCs from the perspective of metabolism,and provided an experimental theory for better understanding of the reasons of bone loss in astronauts under space microgravity conditions.In this study,BMSCs were isolated form SD rats by the method of whole bone marrow adhesion.We modeled the simulated microgravity(SMG)using the clinostat and explored the changes in the osteogenesis and the glycometabolism of BMSCs under SMG conditions.The results showed that the glycometabolsim shifted from glycolysis to OXPHOS during the osteogenesis of BMSCs.Meanwhile,we detected increased expression of histone sirtuin 1(SIRT1).In addition,we found that SMG repressed the osteogenic differentiation of BMSCs accompanied by decreased glycolysis,OXPHOS and the expression of SIRT1.After treatment with resveratrol,the expression of SIRT1 was increased under normal gravity and SMG conditions.Additionally,SMG-inhibited OXPHOS and osteogenesis of BMSCs were recovered after upregulating the expression of SIRT1 using resveratrol.The present study has demonstrated that SMG can inhibit OXPHOS to impair osteogenic differentiation of MSCs,which is possibly due to the decreased expression of SIRT1.Activating OXPHOS by upregulating the expression of SIRT1 could effectively rescue and sustain the osteogenesis of BMSCs under SMG conditions.Our findings suggest that both SIRT1 and OXPHOS could be therapeutic targets for preventing and treating the bone loss in microgravity conditions.