PMID- 32017705 OWN - NLM STAT- MEDLINE DCOM- 20210113 LR - 20210113 IS - 1945-4589 (Electronic) IS - 1945-4589 (Linking) VI - 12 IP - 3 DP - 2020 Feb 3 TI - Insulin impedes osteogenesis of BMSCs by inhibiting autophagy and promoting premature senescence via the TGF-beta1 pathway. PG - 2084-2100 LID - 10.18632/aging.102723 [doi] AB - The dysfunction of bone marrow stromal cells (BMSCs) may be a core factor in Type 2 diabetes mellitus (T2DM) associated osteoporosis. However, the underlying mechanism is not well understood. Here, we delineated the critical role of insulin impeding osteogenesis of BMSCs in T2DM. Compared with BMSCs from healthy people (H-BMSCs), BMSCs from T2DM patient (DM-BMSCs) showed decreased osteogenic differentiation and autophagy level, and increased senescent phenotype. H-BMSCs incubated in hyperglycemic and hyperinsulinemic conditions similarly showed these phenotypes of DM-BMSCs. Notably, enhanced TGF-beta1 expression was detected not only in DM-BMSCs and high-glucose and insulin-treated H-BMSCs, but also in bone callus of streptozocin-induced diabetic rats. Moreover, inhibiting TGF-beta1 signaling not only enhanced osteogenic differentiation and autophagy level of DM-BMSCs, but also delayed senescence of DM-BMSCs, as well as promoted mandible defect healing of diabetic rats. Finally, we further verified that it was TGF-beta receptor II (TbetaRII), not TbetaRI, markedly increased in both DM-BMSCs and insulin-treated H-BMSCs. Our data revealed that insulin impeded osteogenesis of BMSCs by inhibiting autophagy and promoting premature senescence, which it should be responsible for T2DM-induced bone loss, at least in part. These findings suggest that inhibiting TGF-beta1 pathway may be a potential therapeutic target for T2DM associated bone disorders. FAU - Zhang, Ping AU - Zhang P AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. AD - Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. FAU - Zhang, Hengguo AU - Zhang H AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. FAU - Lin, Jialin AU - Lin J AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. FAU - Xiao, Tao AU - Xiao T AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. FAU - Xu, Rongyao AU - Xu R AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. FAU - Fu, Yu AU - Fu Y AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. AD - Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. FAU - Zhang, Yuchao AU - Zhang Y AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. AD - Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. FAU - Du, Yifei AU - Du Y AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. AD - Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. FAU - Cheng, Jie AU - Cheng J AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. AD - Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. FAU - Jiang, Hongbing AU - Jiang H AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. AD - Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200203 PL - United States TA - Aging (Albany NY) JT - Aging JID - 101508617 RN - 0 (Insulin) RN - 0 (TGFB1 protein, human) RN - 0 (Tgfb1 protein, rat) RN - 0 (Transforming Growth Factor beta1) RN - EC 2.7.11.30 (Receptor, Transforming Growth Factor-beta Type II) SB - IM MH - Animals MH - Autophagy/drug effects/*physiology MH - Bony Callus/metabolism MH - Case-Control Studies MH - Cellular Senescence/drug effects/*physiology MH - Diabetes Mellitus, Experimental MH - Diabetes Mellitus, Type 2/complications/*metabolism MH - Female MH - Humans MH - Hyperglycemia MH - Hyperinsulinism MH - Insulin/*metabolism/pharmacology MH - Male MH - Mandible/surgery MH - Mandibular Fractures/diagnostic imaging/metabolism MH - Mesenchymal Stem Cells/drug effects/*metabolism MH - Middle Aged MH - Osteogenesis/drug effects/*physiology MH - Osteoporosis/complications/*metabolism MH - Rats MH - Receptor, Transforming Growth Factor-beta Type II/drug effects/metabolism MH - Transforming Growth Factor beta1/antagonists & inhibitors/*metabolism PMC - PMC7041775 OTO - NOTNLM OT - TGF-beta1 OT - autophagy OT - insulin OT - osteogenesis OT - senescence COIS- CONFLICTS OF INTEREST: All authors declare no conflicts of interest. EDAT- 2020/02/06 06:00 MHDA- 2021/01/14 06:00 PMCR- 2020/02/15 CRDT- 2020/02/05 06:00 PHST- 2019/10/12 00:00 [received] PHST- 2020/01/02 00:00 [accepted] PHST- 2020/02/06 06:00 [pubmed] PHST- 2021/01/14 06:00 [medline] PHST- 2020/02/05 06:00 [entrez] PHST- 2020/02/15 00:00 [pmc-release] AID - 102723 [pii] AID - 10.18632/aging.102723 [doi] PST - ppublish SO - Aging (Albany NY). 2020 Feb 3;12(3):2084-2100. doi: 10.18632/aging.102723. Epub 2020 Feb 3.