Abstract
The endocannabinoid system consists mainly of 2-arachidonoylglycerol and anan-damide, as well as cannabinoid receptor type 1 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.
Original language | English |
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Article number | e65834 |
Journal | eLife |
DOIs | |
Publication status | Published - 23 May 2022 |
Bibliographical note
Funding Information:The authors wish to thank Professor Raphael Mechoulam for his important advice and for providing the HU910 compound. Funding: This work was supported by Israel Science Foundation (ISF) Grants No. 1822/12, 1367/12 and 1086/17, and by an American Society of Bone and Mineral Research (ASBMR) GAP award to Y.G. This work was carried out in partial fulfillment of the requirements for a Ph.D. degree for BR-M from the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Funding Information:
This work was supported by Israel Science Foundation (ISF) Grants No. 1822/12, 1367/12 and 1086/17, and by an American Society of Bone and Mineral Research (ASBMR) GAP award to Y.G. This work was carried out in partial fulfillment of the requirements for a Ph.D. degree for BR-M from the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.