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-ß 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 aVß5, 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 remodeling as a whole. Such insights both provide a greater
understanding of skeletal response to exercise but inform efforts to address bone degenerative diseases by
taking advantage of native signaling pathways.