Delivery of miR-181a/b-1 enhances endochondral fracture repair by targeting PDK4 and regulating mitochondrial metabolism

We previously reported an in vitro pro-osteogenic function for miR-181a/b-1, in part, via increasing mitochondrial metabolism. The goal of this study was to determine the effect of miR-181a/b-1 on bone repair in vivo, and to discover metabolism-related mechanisms. Here we show that local lentiviral delivery of miR-181a/b-1 enhances ulnar fracture repair in male and female mice. We identify a mechanism involving miRNA-mediated targeting of pyruvate dehydrogenase kinase 4 (PDK4), which subsequently increases mitochondrial respiration. The importance of PDK4 regulation is further supported by administration of the PDK4 inhibitor diisopropylamine dichloroacetate (DADA). DADA treatment increases osteogenesis and mitochondrial metabolism in vitro as well as endochondral fracture repair in vivo, similar to the effects of miR-181a/b-1. These findings provide new mechanistic insights into how miR-181a/b-1 positively regulates osteogenesis and fracture repair, and demonstrate potential therapeutic strategies for the treatment of non-healing or delayed-healing fractures.