Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption
Cheng-Chia Tang, Christian Castro, Maureen J. O’Meara, Sung-Hee Yoon, Tadatoshi Sato, Daniel J. Brooks, Mary Bouxsein, Janaina Da Silva Martins, Jinhua Wang, Nathanael S. Gray, Barbara M. Misof, Paul Roschger, Stéphane Blouin, Klaus Klaushofer, Annegreet Velduis-Vlug, Yosta Vegting, Clifford J. Rosen, Daniel J. O’Connell, Thomas B. Sundberg, Ramnik J. Xavier, Peter M.U. Ung, Avner Schlessinger, Henry M. Kronenberg, Rebecca Berdeaux, Marc Foretz, Marc N. Wein
Abstract
Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05-099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here, we report that YKL-05-099 increases bone formation in hypogonadal female mice without increasing bone resorption. Postnatal mice with inducible, global deletion of SIK2 and SIK3 show increased bone mass, increased bone formation, and, distinct from the effects of YKL-05-099, increased bone resorption. No cell-intrinsic role of SIKs in osteoclasts was noted. In addition to blocking SIKs, YKL-05-099 also binds and inhibits CSF1R, the receptor for the osteoclastogenic cytokine M-CSF. Modeling reveals that YKL-05-099 binds to SIK2 and CSF1R in a similar manner. Dual targeting of SIK2/3 and CSF1R induces bone formation without concomitantly increasing bone resorption and thereby may overcome limitations of most current anabolic osteoporosis therapies.