title: Metformin reverses the deleterious effects of high glucose on osteoblast function.
abstract: An association has been previously established between uncompensated diabetes mellitus and the loss of bone mineral density and/or quality. In the present study, we examined the effects of different concentrations of glucose (5.5, 11, 22, and 44 mmol/L) with or without metformin (10-640 micromol/L) on rat primary osteoblasts cultured in an osteogenic medium. With 11 mmol/L glucose, cellular proliferation, alkaline phosphatase (ALP) activity, the number of nodules formed, and calcium deposition in mineralized nodules were increased significantly; intracellular reactive oxygen species (ROS) and apoptosis were slightly reduced, although these reductions were not statistically significant. At higher concentrations of glucose (22 and 44 mmol/L), cellular proliferation, ALP activity, the number of nodules formed, and calcium deposition were greatly reduced; ROS and apoptosis were significantly increased in a dose-dependent manner. Metformin markedly increased cellular proliferation, ALP activity, calcium deposition, and the number of nodules formed and inhibited ROS and apoptosis in all glucose groups. Moreover, we assessed the gene expression levels of Runx2, IGF-1, and IGF-1R. Eleven micromole per liter glucose stimulated Runx2 and IGF-1 expression; 44 mmol/L glucose inhibited Runx2, IGF-1, and IGF-1R expression. Metformin stimulated the expression of Runx2 and IGF-1 in three glucose groups, but it did not affect IGF-1R. In conclusion, our findings suggest that the dual effects of glucose on cell proliferation and development are dose dependent. Metformin not only significantly decreased intracellular ROS and apoptosis, but also had a direct osteogenic effect on osteoblasts at all glucose concentrations, which could be partially mediated via promotion of Runx2 and IGF-1 expression.
authors.affiliation: Department of Life Science, Lanzhou University, Lanzhou, PR China. zhdh8279@gmail.com
authors.forename: Donghu
authors.initials: D
authors.lastname: Zhen
authors.forename: Yirong
authors.initials: Y
authors.lastname: Chen
authors.forename: Xulei
authors.initials: X
authors.lastname: Tang
mesh_terms: D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000008:administration & dosage*; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008687:Metformin / Q000008:administration & dosage*; D010006:Osteoblasts / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000032:analysis
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D007004:Hypoglycemic Agents; D017382:Reactive Oxygen Species; C493717:Runx2 protein, rat; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; D008687:Metformin; D017526:Receptor, IGF Type 1; D000469:Alkaline Phosphatase; D005947:Glucose; D002118:Calcium