Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption
- Massachusetts General Hospital, United States
- Harvard Medical School, United States
- Dana-Farber Cancer Institute, United States
- Hanusch Hospital, Austria
- Leiden University Medical Center, Netherlands
- Academic Medical Center, Netherlands
- Maine Medical Center Research Institute, United States
- Broad Institute of Harvard and MIT, United States
- Broad Institute of MIT and Harvard, United States
- Icahn School of Medicine at Mount Sinai, United States
- Mount Sinai Hospital
- Massachusetts General Hospital and Harvard Medical School, United States
- McGovern Medical School at The University of Texas Health Science Center at Houston, United States
- Université de Paris, France
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.
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Author details
Avner Schlessinger
Funding
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR066261)
- Marc N Wein
National Institute of Diabetes and Digestive and Kidney Diseases (DK116716)
- Marc N Wein
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR067285)
- Marc N Wein
National Institute of Diabetes and Digestive and Kidney Diseases (DK011794)
- Henry M Kronenberg
National Institute of Diabetes and Digestive and Kidney Diseases (DK092590)
- Rebecca Berdeaux
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR059847)
- Rebecca Berdeaux
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures involving animals were performed in accordance with guidelines issued by the Institutional Animal Care and Use Committees (IACUC) in the Center for Comparative Medicine at the Massachusetts General Hospital and Harvard Medical School under approved Animal Use Protocols (2019N000201).
Copyright
© 2021, Tang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption
eLife 10:e67772.
https://doi.org/10.7554/eLife.67772
