Irisin is a novel signaling peptide proteolyzed from the cell membrane-bound protein Fndc5 (fibronectin type III domain-containing protein 5), first described by our collaborators to release from muscle during exercise and induce a thermogenic program in beige adipose tissue. A growing body of work has highlighted another key role for irisin in mediating the effect of exercise on bone. Early work described an anabolic action, with intermittent low doses of irisin stimulating cortical bone formation and preventing unloading-induced bone loss in vivo, and serum-derived irisin from exercised mice enhancing osteoblastogenesis in vitro. Our group has employed a genetic approach to further elucidate the role of irisin in skeletal remodeling, demonstrating that forced expression of Fndc5 in muscle markedly reduced bone formation and osteoblast numbers while increasing sclerostin (SOST) expression and osteoclast numbers. Global genetic deletion of Fndc5 conferred complete protection against ovariectomy-induced bone loss, marked by maintenance of osteocyte lacunae and blocked bone resorption with no increases in Receptor Activator of Nuclear Factor Kappa-β Ligand (RANKL) expression despite prolonged estrogen deprivation. Similarly, short term irisin infusions in wild type mice resulted in higher serum levels of sclerostin and RANKL. These results highlight the breadth of irisin’s signaling effects in bone, and the need to further understand its overall impact on resorption and remodelling. We now have additional evidence that irisin signals directly to the osteoclast via integrin αVβ5, stimulating differentiation and resorption. The present work endeavors to delineate the full signaling pathway in the osteoclast, while employing novel in vivo models to test this regulation of resorption in the context of skeletal response to exercise. We have developed a novel conditional mouse allele of Fndc5 and generated a skeletal muscle- specific targeted null, which we will use to test the effect of muscle-derived irisin on bone response to exercise. In parallel, we will utilize in vitro techniques to confirm the putative receptors for irisin and characterize intracellular signal transduction in the osteoclast. To comprehensively assess irisin’s impact on bone resorption, we will also investigate indirect effects of irisin on the osteoclast, through regulation by the osteocyte. Finally, as osteocyte response to mechanical cues is a key aspect of this cell’s function during exercise, we will investigate the potential interplay between irisin signaling and mechanosensitivity. We predict pleiotropic effects of irisin – it may be a coupling factor by directly stimulating both the osteoblast and osteoclast, and also serve a unique role as a counter regulatory hormone to maintain calcium homeostasis by increasing resorption. By focusing on the osteoclast, this work seeks to elucidate irisin’s role in initiating bone resorption and better understand its influence on remode...