Repair of critical size bone defects is a clinical challenge that usually necessitates the use of bone substitutes. For successful bone repair, the substitute should possess osteoconductive, osteoinductive, and vascularization potential, with the ability to control post-implantation infection serving as an additional advantage. With an aim to develop one such substitute, we optimized a zinc-doped hydroxyapatite (HapZ) nanocomposite decorated on reduced graphene oxide (rGO), termed as G3HapZ, and demonstrated its potential to augment the bone repair. The biocompatible composite displayed its osteoconductive potential in biomineralization studies, and its osteoinductive property was confirmed by its ability to induce mesenchymal stem cell (MSC) differentiation to osteogenic lineage assessed by in vitro mineralization (Alizarin red staining) and expression of osteogenic markers including runt-related transcription factor 2 (RUNX-2), alkaline phosphatase (ALP), type 1 collagen (COL1), bone morphogenic protein-2 (BMP-2), osteocalcin (OCN), and osteopontin (OPN). While the potential of G3HapZ to support vascularization was displayed by its ability to induce endothelial cell migration, attachment, and proliferation, its antimicrobial activity was confirmed using S. aureus. Biocompatibility of G3HapZ was demonstrated by its ability to induce bone regeneration and neovascularization in vivo. These results suggest that G3HapZ nanocomposites can be exploited for a range of strategies in developing orthopedic bone grafts to accelerate bone regeneration.

Liraglutide (Lira), a long-acting glucagon-like peptide 1 receptor (GLP1R) agonist reduces glycosylated hemoglobin in type 2 diabetes mellitus patients. Lira is reported to have bone conserving effect in ovariectomized (OVX) rats. Here, we investigated the osteoanabolic effect of Lira and studied the underlying mechanism. In established osteopenic OVX rats, Lira completely restored bone mass and strength comparable to parathyroid hormone (PTH 1-34). Body mass index normalized bone mineral density of Lira was higher than PTH. The serum levels of osteogenic surrogate pro-collagen type 1 N-terminal pro-peptide (P1NP) and surface referent bone formation parameters were comparable between Lira and PTH. GLP1R, adiponectin receptor 1 (AdipoR1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) levels in bones were down-regulated in the OVX group but restored in the Lira group whereas PTH had no effect. In cultured osteoblasts, Lira time-dependently increased GLP1R, AdipoR1 and PGC1α expression. In osteoblasts, Lira rapidly phosphorylated AMP-dependent protein kinase (AMPK), the cellular energy sensor. Exendin 3, a selective GLP1R antagonist and PKA inhibitor H89 blocked Lira-induced increases in osteoblast differentiation, and expression levels of AdipoR1 and PGC1α. Furthermore, H89 inhibited Lira-induced phosphorylation of AMPK and dorsomorphin, an AMPK inhibitor blocked the Lira-induced increases in osteoblast differentiation and AdipoR1 and PGC1α levels. Lira increased mitochondrial number, respiratory proteins and respiration in osteoblasts in vitro and in vivo, and blocking mitochondrial respiration mitigated *