In vitro effects of metformin and metformin - rosiglitazone co-treatment on rat mesenchymal progenitor cells

SEDLINSKY, CLAUDIA; MOLINUEVO, MARÍA SILVINA; 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

Diabetes mellitus can cause both osteopenia and osteoporosis. It was previously demonstrated that this diabetes-associated bone alterations could be, at least in part, due to pathological accumulation of advanced glycation end-products on bone extracellular matrix proteins. Patients suffering Diabetes mellitus type 2 are treated with oral antidiabetic drugs such as metformin and rosiglitazone as monotherapy or combinated therapy, however there is little information regarding anti-diabetic drugs on bone metabolism. We have previously demonstrated that metformin causes a direct osteogenic action in a model of osteoblast in culture. These actions include a dose dependent increase in cell proliferation and type-I collagen production as well as increases in both alkaline phosphatase activity (ALP) and mineral deposition. On the other hand, it was demonstrated that rosiglitazone not only induce murine bone marrow stromal cell adipogenesis but also inhibit osteogenesis. In vivo, treatment of mice with rosiglitazone decreased bone mineral content, bone formation, and trabecular bone volume, while increasing adipogenesis. In the present work we evaluated the in vitro actions of metformin on bone marrow mesenchymal progenitor cells (BMPC), and the in vitro co-treatment of metformin and rosiglitazone on BMPC. For these in vitro studies BMPC were cultured in an osteoblastic differentiation media (OB media) containing b-glicerophosphate and ascorbic acid. We found that metformin causes a dose dependent increase in mineral deposition after 21 days of culture. On the other hand, we evaluated the effect of metformin on adipogenic capacity of BMPC. BMPC were differentiated to adipocytes in a media containing insulin, dexamethasone and rosiglitazone. We found that metformin inhibited cytoplasmic triacylglicerides deposition. This effect was observed in clinically relevant combinations of rosiglitazone and metformin (2 µg/ml rosiglitazone-500 µg/ml metformin and 2 µg/ml rosiglitazone-1000 µg/ml metformin). In conclusion, our results suggest that metformin promoted osteoblastic differentiation of BMPC. On the other hand, our results also suggest that co-treatment of metformin and rosiglitazone could improve the undesirable side effect (adipogenic) on bone of the last drug however the molecular mechanisms of this action remains to be elucidated.