2. Academic Validation
  3. Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption

Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption

  • Elife. 2021 Jun 23;10:e67772. doi: 10.7554/eLife.67772.
Cheng-Chia Tang 1,  Christian D Castro Andrade 1,  Maureen J O'Meara 1,  Sung-Hee Yoon 1,  Tadatoshi Sato 1,  Daniel J Brooks 1 2,  Mary L Bouxsein 1 2,  Janaina da Silva Martins 1,  Jinhua Wang 3,  Nathanael S Gray 3,  Barbara Misof 4,  Paul Roschger 4,  Stephane Blouin 4,  Klaus Klaushofer 4,  Annegreet Velduis-Vlug 5 6,  Yosta Vegting 7,  Clifford J Rosen 6,  Daniel O'Connell 8,  Thomas B Sundberg 8,  Ramnik J Xavier 8 9,  Peter Ung 10,  Avner Schlessinger 10,  Henry M Kronenberg 1,  Rebecca Berdeaux 11,  Marc Foretz 12,  Marc N Wein 1 8 13
Affiliations

Affiliations

  • 1 Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
  • 2 Center for Advanced Orthopaedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
  • 3 Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
  • 4 Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre, Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria.
  • 5 Center for Bone Quality, Leiden University Medical Center, Leiden, Netherlands.
  • 6 Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, Canada.
  • 7 Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands.
  • 8 Broad Institute of MIT and Harvard, Cambridge, United States.
  • 9 Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, United States.
  • 10 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.
  • 11 Department of Integrative Biology and Pharmacology, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, United States.
  • 12 Université de Paris, Institut Cochin, CNRS, Paris, France.
  • 13 Harvard Stem Cell Institute, Cambridge, United States.
PMID: 34160349 DOI: 10.7554/eLife.67772
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.

Keywords

kinase inhibitor; medicine; mouse; osteocyte; osteoporosis; salt inducible kinase.

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