Diabetic and nondiabetic BMSC-derived exosomes affect bone regeneration via regulating miR-17-5p/SMAD7 axis

Diabetic bone disease (DBD) is a complication of diabetes mellitus (DM) and is characterized by impaired osteocyte function and delayed bone remodeling due to high blood glucose levels and sustained release of inflammatory factors. Recent studies show that the regulation of osteoblasts (OBs) by bone marrow stromal cells (BMSCs) is an important mechanism in alleviating DBD and that exosomes are recognized as the key medium. Mesenchymal stem cell-derived exosome (MSC-Exos) therapy is a promising approach to facilitate tissue repair. However, the influence of exosomes from diabetic conditioned BMSCs on OBs and bone regeneration, as well as the underlying mechanism, are still elusive. Here, we used high-glucose medium to mimic diabetic conditions and normal-glucose medium as control to mimic nondiabetic conditions in vitro and found that microRNA-17 (miR-17) was downregulated in diabetic-conditioned BMSC-derived exosomes (HG-Exos), HG-Exo-co-cultured osteoblasts, and the skull of rats with type 2 diabetes mellitus (T2DM). Further experiment concluded that nondiabetic conditioned BMSC-Exos (NG-Exos) promoted the osteogenesis of OBs and bone regeneration of rats with T2DM via upregulation of miR-17. Compare with NG-Exos, HG-Exos impeded osteogenesis of OBs in vitro and bone regeneration of rats in vivo by downregulation of miR-17. Moreover, miR-17 promoted bone regeneration by targeting SMAD7, which was further proved to have a negative effect on osteogenesis. Taken together, nondiabetic BMSC-derived exosomes greatly foster bone regeneration, whereas diabetic BMSC-derived exosomes undermine the promotion effect of MSC-Exos by regulating the miR-17/SMAD7 axis. These findings provide support for the miR-17-5p/SMAD7 axis as a promising therapeutic target to treat DBD.