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

  1. Cheng-Chia Tang
  2. Christian D Castro Andrade
  3. Maureen J O'Meara
  4. Sung-Hee Yoon
  5. Tadatoshi Sato
  6. Daniel J Brooks
  7. Mary L Bouxsein
  8. Janaina da Silva Martins
  9. Jinhua Wang
  10. Nathanael S Gray
  11. Barbara Misof
  12. Paul Roschger
  13. Stephane Boulin
  14. Klaus Klaushofer
  15. Annegreet Velduis-Vlug
  16. Yosta Vegting
  17. Clifford J Rosen
  18. Daniel O'Connell
  19. Thomas B Sundberg
  20. Ramnik J Xavier
  21. Peter Ung
  22. Avner Schlessinger
  23. Henry M Kronenberg
  24. Rebecca Berdeaux
  25. Marc Foretz
  26. Marc N Wein  Is a corresponding author
  1. Massachusetts General Hospital, United States
  2. Harvard Medical School, United States
  3. Dana-Farber Cancer Institute, United States
  4. Hanusch Hospital, Austria
  5. Leiden University Medical Center, Netherlands
  6. Academic Medical Center, Netherlands
  7. Maine Medical Center Research Institute, United States
  8. Broad Institute of Harvard and MIT, United States
  9. Broad Institute of MIT and Harvard, United States
  10. Icahn School of Medicine at Mount Sinai, United States
  11. Mount Sinai Hospital
  12. Massachusetts General Hospital and Harvard Medical School, United States
  13. McGovern Medical School at The University of Texas Health Science Center at Houston, United States
  14. 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.

Data availability

Source data files have been provided for all figures.

Article and author information

Author details

  1. Cheng-Chia Tang

    Endocrine Unit, Massachusetts General Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  2. Christian D Castro Andrade

    Endocrine Unit, Massachusetts General Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  3. Maureen J O'Meara

    Endocrine Unit, Massachusetts General Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  4. Sung-Hee Yoon

    Endocrine Unit, Massachusetts General Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  5. Tadatoshi Sato

    Endocrine Unit, Massachusetts General Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  6. Daniel J Brooks

    Endocrine Unit, Massachusetts General Hospital, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7408-9851
  7. Mary L Bouxsein

    Medicine, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  8. Janaina da Silva Martins

    Endocrine Unit, Massachusetts General Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  9. Jinhua Wang

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  10. Nathanael S Gray

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5354-7403
  11. Barbara Misof

    Ludwig Boltzmann Institute of Osteology, Hanusch Hospital, Vienna, Austria
    Competing interests
    No competing interests declared.
  12. Paul Roschger

    Ludwig Boltzmann Institute of Osteology, Hanusch Hospital, Vienna, Austria
    Competing interests
    No competing interests declared.
  13. Stephane Boulin

    Ludwig Boltzmann Institute of Osteology, Hanusch Hospital, Vienna, Austria
    Competing interests
    No competing interests declared.
  14. Klaus Klaushofer

    Ludwig Boltzmann Institute of Osteology, Hanusch Hospital, Vienna, Austria
    Competing interests
    No competing interests declared.
  15. Annegreet Velduis-Vlug

    Center for Bone Quality, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
  16. Yosta Vegting

    Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  17. Clifford J Rosen

    Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, United States
    Competing interests
    No competing interests declared.
  18. Daniel O'Connell

    Center for the development of therapeutics, Broad Institute of Harvard and MIT, Cambridge, United States
    Competing interests
    No competing interests declared.
  19. Thomas B Sundberg

    Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    No competing interests declared.
  20. Ramnik J Xavier

    Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    Ramnik J Xavier, MNW, HMK, TBS, RJX, and NSG are co-inventors on a pending patent (US Patent Application 16/333,546) regarding the use of SIK inhibitors for osteoporosis..
  21. Peter Ung

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York City, United States
    Competing interests
    Peter Ung, Peter M.U. Ung is currently affiliated with Genentech. The author has no financial interests to declare..
  22. Avner Schlessinger

    Mount Sinai Hospital
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4007-7814
  23. Henry M Kronenberg

    Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  24. Rebecca Berdeaux

    Department of Integrative Biology and Pharmacology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, United States
    Competing interests
    No competing interests declared.
  25. Marc Foretz

    Institut Cochin, Université de Paris, Paris, France
    Competing interests
    No competing interests declared.
  26. Marc N Wein

    Endocrine Unit, Massachusetts General Hospital, Boston, United States
    For correspondence
    MNWEIN@mgh.harvard.edu
    Competing interests
    Marc N Wein, MNW, HMK, TBS, RJX, and NSG are co-inventors on a pending patent (US Patent Application 16/333,546) regarding the use of SIK inhibitors for osteoporosis. MNW receives research support from Radius Health. MNW and HMK receive research support from Galapagos NV..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6015-8147

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).

Reviewing Editor

  1. Ernestina Schipani, University of Pennsylvania, United States

Publication history

  1. Received: February 22, 2021
  2. Accepted: June 16, 2021
  3. Accepted Manuscript published: June 23, 2021 (version 1)
  4. Version of Record published: June 28, 2021 (version 2)

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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  1. Cheng-Chia Tang
  2. Christian D Castro Andrade
  3. Maureen J O'Meara
  4. Sung-Hee Yoon
  5. Tadatoshi Sato
  6. Daniel J Brooks
  7. Mary L Bouxsein
  8. Janaina da Silva Martins
  9. Jinhua Wang
  10. Nathanael S Gray
  11. Barbara Misof
  12. Paul Roschger
  13. Stephane Boulin
  14. Klaus Klaushofer
  15. Annegreet Velduis-Vlug
  16. Yosta Vegting
  17. Clifford J Rosen
  18. Daniel O'Connell
  19. Thomas B Sundberg
  20. Ramnik J Xavier
  21. Peter Ung
  22. Avner Schlessinger
  23. Henry M Kronenberg
  24. Rebecca Berdeaux
  25. Marc Foretz
  26. Marc N Wein
(2021)
Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption
eLife 10:e67772.
https://doi.org/10.7554/eLife.67772

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