Abstract
Metformin, the gold standard in type 2 diabetes treatment, is a drug with multi-faceted effects. Currently, metformin has gained much attention as an agent that may find application in regenerative medicine. In this study, we considered its pro-osteogenic function in the course of in vitro osteogenesis of multipotent stromal cells derived from rat adipose tissue (rASCs). In addition, we evaluated the effect of metformin treatment on bone metabolism in a model of cranial defect in nondiabetic rats. In vitro study showed that metformin that is introduced to the culture medium at concentration equal 500 µM may promote the differentiation of rASCs into bone-forming cells, which express mRNA and secrets proteins that are related to the functional tissue (namely, alkaline phosphatase and osteocalcin). Osteogenic effect of metformin, as determined using in vitro model, was also manifested with the formation of mineralized extracellular matrix rich calcium and phosphorous deposits. We have also found, that in undifferentiated rASCs, metformin significantly activates a critical regulatory factor for osteogenic differentiation, i.e., AMPK. Moreover, using in vivo model we showed metformin administration at a dose of 250 mg/kg/day accelerated bone healing and the formation of mature tissue at a fracture site in rat cranial defect model. The obtained results shed promising light on metformin application in regenerative orthopedics, both as an agent improving functionality of ASCs for therapeutic transplantation, as well as a medication enhancing the bone healing process.
Highlights
Bone fractures are a significant health problem—for the individual and for the society alike
Immunophenotyping of Rat Adipose-Derived Multipotent Mesenchymal Stromal Cells (rASC) showed that cells used for the experiment were characterized by the presence of surface markers specific for multipotent mesenchymal stromal cells i.e., CD43, CD73, CD90, and CD105
Specific staining showed that the propagation of rASCs in the proper differentiation medium promotes the formation of lipid droplets (Oil-Red O), cartilage nodules (Safranin-O), and formation of calcium-rich deposits (Alizarin Red) (Figure 1B)
Summary
Bone fractures are a significant health problem—for the individual and for the society alike. Activity of Akt and AMPK are inversely correlated, as was demonstrated by the Pantovic et al who showed that AMPK may control osteogenic differentiation of human MSC’s through late activation of Akt [21] It seems that the protective effects exerted on bone tissue might be associated with the anti-adipogenic effects of metformin [22]. Since metformin was reported as an agent inducing osteogenic differentiation of BMSCs in a dose-dependent manner, in the present study we decided to determine its effect on ASCs. We hypothesized that metformin, at a defined concentration, may trigger in vitro osteogenic differentiation of ASCs. The overarching goal of our experiment was to address the role of metformin in fracture healing. The obtained results shed promising light on metformin application in regenerative orthopedics, both as an agent improving functionality of ASCs for therapeutic transplantation, as well as a medication enhancing the bone healing process
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