TY - JOUR
T1 - Dual targeting of salt inducible kinases and csf1r uncouples bone formation and bone resorption
AU - Tang, Cheng-Chia
AU - Andrade, Christian D. Castro
AU - O’meara, Maureen J.
AU - Yoon, Sung-Hee
AU - Sato, Tadatoshi
AU - Brooks, Daniel J.
AU - Bouxsein, Mary L.
AU - Martins, Janaina da Silva
AU - Wang, Jinhua
AU - Gray, Nathanael S.
AU - Misof, Barbara
AU - Roschger, Paul
AU - Boulin, Stephane
AU - Klaushofer, Klaus
AU - Velduis-Vlug, Annegreet
AU - Vegting, Yosta
AU - Rosen, Clifford J.
AU - O’connell, Daniel
AU - Sundberg, Thomas B.
AU - Xavier, Ramnik J.
AU - Ung, Peter
AU - Schlessinger, Avner
AU - Kronenberg, Henry M.
AU - Berdeaux, Rebecca
AU - Foretz, Marc
AU - Wein, Marc N.
N1 - Funding Information: We thank Drs. Michael Mannstadt, Lauren Surface, Francesca Gori, Tatsuya Kobayashi, Mark Poznan-sky, Christiana Iyasere, and members of the Wein laboratory for helpful discussions. MNW acknowledges funding support from the American Society of Bone and Mineral Research, the Harrington Discovery Institute, the MGH Department of Medicine Innovation Program, the Gillian Reny Stepping Strong Center for Trauma Innovatio, and the National Institute of Health (DK116716, AR066261, and AR067285). HMK acknowledges funding support from the National Institute of Health (AR066261 and DK011794). MF acknowledges funding support from Centre National de la Recherche Scientifique (CNRS), the Société Francophone du Diabète (SFD) and the Fondation pour la Recherche Médicale (FRM). RB acknowledges funding support from the National Institutes of Health (DK092590 and AR059847). Publisher Copyright: © Tang et al.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108897743&partnerID=8YFLogxK
U2 - https://doi.org/10.7554/eLife.67772
DO - https://doi.org/10.7554/eLife.67772
M3 - Article
C2 - 34160349
SN - 2050-084X
VL - 10
JO - eLife
JF - eLife
M1 - e67772
ER -