Metformin co-treatment reverts anti-osteogenic effects of rosiglitazone in rats

SEDLINSKY, CLAUDIA; MOLINUEVO, MARÍA SILVINA; SCHURMAN, LEON; MCCARTHY, ANTONIO DESMOND; FELICE, JUAN IGNACIO; GANGOITI, MARÍA VIRGINIA; TOLOSA, MARÍA JOSÉ ANAHÍ; CORTIZO, ANA MARÍA

Washington DC

Encuentro; The Endocrine Society's 91st Annual Meeting; 2009

The Endocrine Society

In the present work, we evaluated the ex-vivo actions of metformin (MET) and/or rosiglitazone (RGZ) treatment on the osteogenic potential of bone marrow progenitor cells (BMPC), as well as the in vivo effect of these insulin-sensitizers on the reossification of a parietal bone lesion. For this purpose, a 1 mm circular bone lesion was performed under anesthesia on the parietal bone of young male Sprague Dawley rats. Rats were then separated into four groups: control, receiving water ad libitum; MET, receiving 100 mg/kg/day MET in drinking water; RGZ, receiving 4 mg/kg/day RGZ in drinking water and METRGZ, receiving 100 mg/kg/day MET plus 4 mg/kg/day RGZ in drinking water. After 30 days of treatment, all the rats were sacrificed under anesthesia. For the in vivo studies, parietal bones were processed for histological evaluation of reossification activity in the bone lesion (area of new bone formation / parietal thickness). For the ex-vivo studies, BMPC were isolated from the femoral bone marrow of rats from all four groups and cultured for 15 or 21 days in osteogenic media, in order to evaluate type-I collagen production and extracellular mineral deposition. Histological examination of parietal bones showed that MET treatment significantly increased reossification activity versus control (207 + 16 % of control) while RGZ greatly inhibited new bone formation in the parietal lesion (18 + 4 % of control). In rats treated with both insulin-sensitizers, MET completely reversed the inhibitory action of RGZ on bone reossification (90 + 10 % of control). Results of the ex-vivo studies showed that MET induced a dose-dependent increase in BMPC type-I collagen production and mineral deposition after 15 or 21 days of culture respectively (359 + 35 and 237 + 18 % of control) whereas RGZ had an inhibitory effect (133 + 23 and 76 + 4 % of control). However, in rats treated with both insulin-sensitizers, MET partially reversed the inhibitory action of RGZ on collagen and mineral deposition (150 + 13 and 201 + 18 % of control). In conclusion, our results suggest that MET can directly increase both osteoblastic commitment of BMPC and bone tissue regeneration, as opposed to the pro-adipogenic and anti-osteogenic actions of RGZ. Our results also suggest that co-treatment with both insulin-sensitizers could improve the undesirable side effects of RGZ on bone. The molecular mechanisms of action of these effects remain to be elucidated.