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.

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.

Reviewing Editor

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

Publication 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.

Metrics

  • 1,124
    Page views
  • 178
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Computational and Systems Biology
    2. Neuroscience
    Zhe Chen, Garrett J Blair ... Hugh T Blair
    Tools and Resources

    Epifluorescence miniature microscopes ('miniscopes') are widely used for in vivo calcium imaging of neural population activity. Imaging data is typically collected during a behavioral task and stored for later offline analysis, but emerging techniques for online imaging can support novel closed-loop experiments in which neural population activity is decoded in real time to trigger neurostimulation or sensory feedback. To achieve short feedback latencies, online imaging systems must be optimally designed to maximize computational speed and efficiency while minimizing errors in population decoding. Here we introduce DeCalciOn, an open-source device for real-time imaging and population decoding of in vivo calcium signals that is hardware compatible with all miniscopes that use the UCLA Data Acquisition (DAQ) interface. DeCalciOn performs online motion stabilization, neural enhancement, calcium trace extraction, and decoding of up to 1024 traces per frame at latencies of <50 ms after fluorescence photons arrive at the miniscope image sensor. We show that DeCalciOn can accurately decode the position of rats (n=12) running on a linear track from calcium fluorescence in the hippocampal CA1 layer, and can categorically classify behaviors performed by rats (n=2) during an instrumental task from calcium fluorescence in orbitofrontal cortex (OFC). DeCalciOn achieves high decoding accuracy at short latencies using innovations such as field-programmable gate array (FPGA) hardware for real time image processing and contour-free methods to efficiently extract calcium traces from sensor images. In summary, our system offers an affordable plug-and-play solution for real-time calcium imaging experiments in behaving animals.

    1. Computational and Systems Biology
    2. Immunology and Inflammation
    Anastasia O Smirnova, Anna M Miroshnichenkova ... Alexander Komkov
    Tools and Resources

    High-throughput sequencing of adaptive immune receptor repertoires is a valuable tool for receiving insights in adaptive immunity studies. Several powerful TCR/BCR repertoire reconstruction and analysis methods have been developed in the past decade. However, detecting and correcting the discrepancy between real and experimentally observed lymphocyte clone frequencies is still challenging. Here we discovered a hallmark anomaly in the ratio between read count and clone count-based frequencies of non-functional clonotypes in multiplex PCR-based immune repertoires. Calculating this anomaly, we formulated a quantitative measure of V- and J-genes frequency bias driven by multiplex PCR during library preparation called Over Amplification Rate (OAR). Based on the OAR concept, we developed an original software for multiplex PCR-specific bias evaluation and correction named iROAR: Immune Repertoire Over Amplification Removal (https://github.com/smiranast/iROAR). The iROAR algorithm was successfully tested on previously published TCR repertoires obtained using both 5' RACE (Rapid Amplification of cDNA Ends)-based and multiplex PCR-based approaches and compared with a biological spike-in-based method for PCR bias evaluation. The developed approach can increase the accuracy and consistency of repertoires reconstructed by different methods making them more applicable for comparative analysis.