GIOMM (Grupo de Investigación en Osteopatías y Metabolismo Mineral), Department of Biological Sciences, School of Exact Sciences, National University of La Plata, La Plata, Argentina.
Eur J Pharmacol. 2011 Oct 15;668(3):477-85. doi: 10.1016/j.ejphar.2011.07.033. Epub 2011 Aug 5.
Long-term treatment with the insulin-sensitizer rosiglitazone reduces bone mass and increases fracture risk. We have recently shown that orally administered metformin stimulates bone reossification and increases the osteogenic potential of bone marrow progenitor cells (BMPC). In the present study we investigated the effect of a 2-week metformin and/or rosiglitazone treatment on bone repair, trabecular bone microarchitecture and BMPC osteogenic potential, in young male Sprague-Dawley rats. Compared to untreated controls, rosiglitazone monotherapy decreased bone regeneration, femoral metaphysis trabecular area, osteoblastic and osteocytic density, and TRAP activity associated with epiphyseal growth plates. It also decreased the ex vivo osteogenic commitment of BMPC, inducing an increase in PPARγ expression, and a decrease in Runx2/Cbfa1 expression, in AMP-kinase phosphorylation, and in osteoblastic differentiation and mineralization. After monotherapy with metformin, with the exception of PPARγ expression which was blunted, all of the above parameters were significantly increased (compared to untreated controls). Metformin/rosiglitazone co-treatment prevented all the in vivo and ex vivo anti-osteogenic effects of rosiglitazone monotherapy, with a reversion back to control levels of PPARγ, Runx2/Cbfa1 and AMP-kinase phosphorylation of BMPC. In vitro co-incubation of BMPC with metformin and compound C-an inhibitor of AMPK phosphorylation-abrogated the metformin-induced increase in type-1 collagen production, a marker of osteoblastic differentiation. In conclusion, in rodent models metformin not only induces direct osteogenic in vivo and ex vivo actions, but when it is administered orally in combination with rosiglitazone it can prevent several of the adverse effects that this thiazolidenedione shows on bone tissue.
长期使用胰岛素增敏剂罗格列酮会降低骨量并增加骨折风险。我们最近表明，口服二甲双胍可刺激骨再矿化并增加骨髓祖细胞（BMPC）的成骨潜能。在本研究中，我们研究了 2 周的二甲双胍和/或罗格列酮治疗对年轻雄性 Sprague-Dawley 大鼠骨修复、小梁骨微观结构和 BMPC 成骨潜能的影响。与未治疗的对照组相比，罗格列酮单药治疗降低了骨再生、股骨干骺端小梁面积、成骨细胞和破骨细胞密度，以及与骺板相关的 TRAP 活性。它还降低了 BMPC 的体外成骨承诺，诱导 PPARγ表达增加，Runx2/Cbfa1 表达减少，AMP-激酶磷酸化减少，成骨分化和矿化减少。在单独使用二甲双胍治疗后，除了 PPARγ 表达受到抑制外，所有上述参数均显著增加（与未治疗的对照组相比）。二甲双胍/罗格列酮联合治疗可预防罗格列酮单药治疗的所有体内和体外抗成骨作用，使 BMPC 的 PPARγ、Runx2/Cbfa1 和 AMP-激酶磷酸化恢复到对照水平。体外共培养 BMPC 与二甲双胍和化合物 C-AMPK 磷酸化抑制剂-消除了二甲双胍诱导的 1 型胶原蛋白产生的增加，这是成骨分化的标志物。总之，在啮齿动物模型中，二甲双胍不仅诱导体内和体外直接成骨作用，而且当它与罗格列酮联合口服给药时，它可以预防这种噻唑烷二酮对骨骼组织产生的几种不良影响。
