Osteogenic growth peptide is a potent anti-inflammatory and bone preserving hormone via cannabinoid receptor type 2
- Tel Aviv University, Israel
- Hebrew University of Jerusalem, Israel
- University of Aberdeen, United Kingdom
- Weizmann Institute of Science, Israel
- 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
Bitya Raphael-Mizrahi
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.
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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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
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