SIRT7 Regulates The Osteogenesis And Angiogenesis Of BMMSCs To Promote Bone Regeneration

Sirtuin family are NAD-dependent histone deacetylases,which have diverse roles in aging,DNA repair,cell cycle,metabolism,and disease biology.Many studies showed that SIRT1,SIRT3 and SIRT6 were involved in the osteogenic differentiation of stem cell and promoted bone regeneration.SIRT7 is a member of the sirtuin family,binds to the ribosomal RNA gene and is associated with reactivation of ribosomal DNA transcription following mitosis.In a previous study,human bone marrow mesenchymal stem cells(hBMMSCs)with reduced SIRT7 activity were developed to evaluate the effect of SIRT7 on osteogenesis.SIRT7 knockdown significantly enhanced osteoblast-specific gene and protein expression,alkaline phosphatase activity,and mineral deposition in vitro.Additionally,SIRT7 knockdown upregulated β-catenin.The enhanced osteogenesis due to SIRT7 knockdown was partially rescued by a Wnt/β-catenin inhibitor.Furthermore,SIRT7 knockdown hBMMSCs combined with a chitosan scaffold significantly promoted bone formation in a rat tibial defect model,as determined by imaging and histological examinations.We found SIRT7 knockdown significantly promoted hBMMSCs to secret vascular endothelial growth factor A(VEGF-A).SIRT7 knockdown upregulated HIF-1α,which in favored the expression of VEGF-A.Furthermore,we collected the culture media from SIRT7 knockdown hBMMSCs to form the new conditional media,which was used in the angiogenesis of human umbilical vein endothelial cells(HUVECs).The conditional media from SIRT7 knockdown cells significantly enhanced the proliferation,migration,and tube formation of HUVECs.The enhanced angiogenesis due to SIRT7 knockdown was partially rescued by a VEGF-A neutralizing antibody in the conditional media.These findings suggest that SIRT7 has an essential role in osteogenic differentiation and angiogenesis of hBMMSCs for bone regeneration.