Hyeonwoo Kim,^1,2 Christiane D. Wrann,^1,2,3,4 Mark Jedrychowski,^1,2 Sara Vidoni,^1,2 Yukiko Kitase,⁵ Kenichi Nagano,⁶ Chenhe Zhou,⁶ Joshua Chou,⁶ Virginia-Jeni A. Parkman,⁶ Scott J. Novick,7 Timothy S. Strutzenberg,⁷ Bruce D. Pascal,⁷ Phuong T. Le,8 Daniel J. Brooks,⁹ Alexander M. Roche,^1,2 Kaitlyn K. Gerber,^1,2 Laura Mattheis,^1,2 Wenjing Chen,10 Hua Tu,¹⁰ Mary L. Bouxsein,^9,11 Patrick R. Griffin,⁷ Roland Baron,^4,6 Clifford J. Rosen,⁸ Lynda F. Bonewald,^5,12 and Bruce M. Spiegelman<sup>1,2,13,*

1</sup> Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
² Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA
³ Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02219, USA
⁴ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
⁵ Department of Anatomy and Cell Biology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
⁶ Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA
⁷ Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA
⁸ Maine Medical Center Research Institute, Scarborough, ME 04074, USA
⁹ Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
¹⁰ LakePharma, Inc., San Carlos, CA 94070, USA
¹¹ Department of Orthopedic Surgery, Harvard Medical School, Boston, MA 02215, USA
¹² Department of Orthopedic Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
¹³ Lead Contact

^*Correspondence : Bruce M. Spiegelman

Irisin is secreted by muscle, increases with exercise, and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear, and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins, and biophysical studies identify interacting surfaces between irisin and αV/β5 integrin. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Genetic ablation of FNDC5 (or irisin) completely blocks osteocytic osteolysis induced by ovariectomy, preventing bone loss and supporting an important role of irisin in skeletal remodeling. Identification of the irisin receptor should greatly facilitate our understanding of irisin’s function in exercise and human health.