Osteogenic growth peptide is a potent anti-inflammatory and bone preserving hormone via cannabinoid receptor type 2

  1. Bitya Raphael-Mizrahi  Is a corresponding author
  2. Malka Attar-Lamdar
  3. Mukesh Chourasia
  4. Maria G Cascio
  5. Avital Shurki
  6. Joseph Tam
  7. Moshe Neuman
  8. Neta Rimmerman
  9. Zvi Vogel
  10. Arie Shteyer
  11. Roger G Pertwee
  12. Andreas Zimmer
  13. Natalya Kogan
  14. Itai Bab
  15. Yankel Gabet  Is a corresponding author
  1. Tel Aviv University, Israel
  2. Hebrew University of Jerusalem, Israel
  3. University of Aberdeen, United Kingdom
  4. Weizmann Institute of Science, Israel
  5. University of Bonn, Germany

Abstract

The endocannabinoid system consists mainly of 2-arachidonoylglycerol and anandamide, as well as cannabinoid receptor type 1 (CB1) and type 2 (CB2). Based on previous studies, we hypothesized that a circulating peptide previously identified as Osteogenic Growth Peptide (OGP) maintains a bone-protective CB2 tone. We tested OGP activity in mouse models and cells, and in human osteoblasts. We show that the OGP effects on osteoblast proliferation, osteoclastogenesis, and macrophage inflammation in vitro, as well as rescue of ovariectomy-induced bone loss and prevention of ear edema in vivo are all abrogated by genetic or pharmacological ablation of CB2. We also demonstrate that OGP binds at CB2 and may act as both an agonist and positive allosteric modulator in the presence of other lipophilic agonists. In premenopausal women, OGP circulating levels significantly decline with age. In adult mice, exogenous administration of OGP completely prevented age-related bone loss. Our findings suggest that OGP attenuates age-related bone loss by maintaining a skeletal CB2 tone. Importantly, they also indicate the occurrence of an endogenous peptide that signals via CB2 receptor in health and disease.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1 and 2 and 4-8.

Article and author information

Author details

  1. Bitya Raphael-Mizrahi

    Department of Anatomy and Anthropology, Tel Aviv University, Tel Aviv, Israel
    For correspondence
    bityar@tau.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8629-1088
  2. Malka Attar-Lamdar

    Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Mukesh Chourasia

    Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Maria G Cascio

    Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Avital Shurki

    Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Joseph Tam

    Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0948-0093
  7. Moshe Neuman

    Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Neta Rimmerman

    Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  9. Zvi Vogel

    Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  10. Arie Shteyer

    Department of Oral and Maxillofacial Surgery, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  11. Roger G Pertwee

    Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Andreas Zimmer

    Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Natalya Kogan

    Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  14. Itai Bab

    Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  15. Yankel Gabet

    Department of Anatomy and Anthropology, Tel Aviv University, Tel Aviv, Israel
    For correspondence
    yankel@tauex.tau.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7494-0631

Funding

Israel Science Foundation (1822/12)

  • Yankel Gabet

Israel Science Foundation (1367/12)

  • Yankel Gabet

Israel Science Foundation (1086/17)

  • Yankel Gabet

American Society for Bone and Mineral Research (Gap award)

  • Yankel Gabet

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States

Ethics

Animal experimentation: Animals - C57BL/6J mice were used in all experiments. All procedures involving animals were carried out in accordance with the institutional guidelines and were approved by the Institutional Animal Care and Use Committee of Tel Aviv University (permit number M-14-092) and the Hebrew University of Jerusalem (permit number MD-12-13458-3). Cnr2 knockout (Cnr2-/-) were generated and shipped from the University of Bonn (Germany) and bred in the respective animal facilities at the Hebrew University and Tel Aviv University (SPF unit).

Human subjects: Human osteoblasts - The cells were obtained from patients undergoing total hip replacement (Helsinki ethics approval 0063-12-TLV).Human serum - The protocol was designed in accordance the institutional guidelines and with the approval of the Institutional Research Committee for Human Studies of the Hebrew University-Hadassah Medical Centre.We declare that a written informed consent was received from all participants prior to inclusion in this study.

Version history

  1. Received: December 16, 2020
  2. Accepted: May 22, 2022
  3. Accepted Manuscript published: May 23, 2022 (version 1)
  4. Version of Record published: May 31, 2022 (version 2)
  5. Version of Record updated: June 1, 2022 (version 3)

Copyright

© 2022, Raphael-Mizrahi 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. Bitya Raphael-Mizrahi
  2. Malka Attar-Lamdar
  3. Mukesh Chourasia
  4. Maria G Cascio
  5. Avital Shurki
  6. Joseph Tam
  7. Moshe Neuman
  8. Neta Rimmerman
  9. Zvi Vogel
  10. Arie Shteyer
  11. Roger G Pertwee
  12. Andreas Zimmer
  13. Natalya Kogan
  14. Itai Bab
  15. Yankel Gabet
(2022)
Osteogenic growth peptide is a potent anti-inflammatory and bone preserving hormone via cannabinoid receptor type 2
eLife 11:e65834.
https://doi.org/10.7554/eLife.65834

Share this article

https://doi.org/10.7554/eLife.65834

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