Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture

• DOI: 10.1016/j.ejphar.2006.02.030
• Publication Date: 2006-03-01T18:46:10Z
• Authors: Ana M. Cortizo; Claudia Sedlinsky; Antonio D. McCarthy; Alcira Blanco; León Schurman
• Keywords: Nitric Oxide Synthase Type III; Nitric Oxide Synthase Type II; Osteoblastos; Collagen Type I; Cell Line; 03 medical and health sciences; Diabetes mellitus; Osteogenesis; Cell Line, Tumor; Metformin; Osteoblast; Osteoporosis; Diabetes mellitus; Diabetes Mellitus; Animals; Hypoglycemic Agents; Phosphorylation; Metformina; Ciencias Exactas; Cell Proliferation; Mitogen-Activated Protein Kinase 1; 0303 health sciences; Mitogen-Activated Protein Kinase 3; Osteoblasts; Dose-Response Relationship, Drug; Osteoblast; Ciencias Químicas; Cell Differentiation; Alkaline Phosphatase; Metformin; Microscopy, Fluorescence; Osteoporosis

An association has been previously established between uncompensated diabetes mellitus and the loss of bone mineral density and/or quality. In this study, we evaluated the effects of metformin on the growth and differentiation of osteoblasts in culture. Treatment of two osteoblast-like cells (UMR106 and MC3T3E1) with metformin (25-500 microM) for 24 h led to a dose-dependent increase of cell proliferation. Metformin also promoted osteoblastic differentiation: it increased type-I collagen production in both cell lines and stimulated alkaline phosphatase activity in MC3T3E1 osteoblasts. In addition, metformin markedly increased the formation of nodules of mineralization in 3-week MC3T3E1 cultures. Metformin induced activation and redistribution of phosphorylated extracellular signal-regulated kinase (P-ERK) in a transient manner, and dose-dependently stimulated the expression of endothelial and inducible nitric oxide synthases (e/iNOS). These results show for the first time a direct osteogenic effect of metformin on osteoblasts in culture, which could be mediated by activation/redistribution of ERK-1/2 and induction of e/iNOS.