In vivo and in vitro effects of metformin on osteoblastic differentiation of bone marrow mesenchymal progenitor cells

MOLINUEVO, MARÍA SILVINA; SEDLINSKY, CLAUDIA; TOLOSA, MARÍA JOSÉ ANAHÍ; MCCARTHY, ANTONIO DESMOND; SCHURMAN, LEON; CORTIZO, ANA MARÍA

San Francisco

Encuentro; The Endocrine Society's Annual Meeting 2008; 2008

The Endocrine Society

Metformin is an insulin-sensitizer drug widely used in conditions associated with insulin-resistance such as type 2 diabetes. The UK Prospective Diabetes Study (UKPDS) showed that metformin treatment reduces the risk of life-threatening macrovascular complications compared to other anti-hyperglycaemic agents. Metformin was shown to inhibit cytosolic and mitocondrial reactive oxygen species production induced by AGEs in endothelial and smooth muscle cells. We have shown that metformin induces a dose-dependent increase in cell proliferation, differentiation and mineralization in two osteoblast cell lines (UMR106 and MC3T3E1), probably mediated by activation and redistribution of ERK 1/2 and induction of eNOS and iNOS. We have recently demonstrated that metformin is able to prevent the increase in apoptosis, inhibition of ALP and alterations in intracellular oxidative stress induced by AGEs in osteoblastic cells and that AGEs-RAGE interaction was implicated in this modulation of the growth and differentiation of osteoblasts. In the present work we evaluated the in vivo and in vitro actions of metformin on bone marrow mesenchymal progenitor cells (BMPC). This in vivo experiment was carried out treating Spraw-Drawley rats with 100 mg/kg/day metformin during 15 days. After that period, rats were sacrified and BMPC were obtained from femur and tibiae. Control rats, without metformin treatment, were also included. After 15 days of culture ALP activity of BMPC obtained from both metformin-treated and no-treated rats were analyzed. We found that BMPC from metformin-treated rats expressed higher levels of ALP activity than BMPC from non-treated rats (~ 2 fold increase). When BMPC of both origins were cultured in OB media for 15 days we found that BMPC from metformin-treated rats expressed higher levels of ALP activity than non-treated BMPC (basal) (164 + 10 % Basal, p<0.001). In agreement with this result, after 21 days under OB differentiation culture conditions BMPC from metformin-treated rats caused higher mineralization of extracellular matrix than BMPC from non-treated rats, (127 + 9%  p<0.05). In conclusion, our results suggest that in vivo and in vitro, metformin promoted osteoblastic differentiation of BMPC.