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.
Metrics
-
- 1,988
- views
-
- 250
- downloads
-
- 7
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
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
-
- Computational and Systems Biology
- Neuroscience
The basolateral amygdala (BLA) is a key site where fear learning takes place through synaptic plasticity. Rodent research shows prominent low theta (~3–6 Hz), high theta (~6–12 Hz), and gamma (>30 Hz) rhythms in the BLA local field potential recordings. However, it is not understood what role these rhythms play in supporting the plasticity. Here, we create a biophysically detailed model of the BLA circuit to show that several classes of interneurons (PV, SOM, and VIP) in the BLA can be critically involved in producing the rhythms; these rhythms promote the formation of a dedicated fear circuit shaped through spike-timing-dependent plasticity. Each class of interneurons is necessary for the plasticity. We find that the low theta rhythm is a biomarker of successful fear conditioning. The model makes use of interneurons commonly found in the cortex and, hence, may apply to a wide variety of associative learning situations.
-
- Cancer Biology
- Computational and Systems Biology
Effects from aging in single cells are heterogenous, whereas at the organ- and tissue-levels aging phenotypes tend to appear as stereotypical changes. The mammary epithelium is a bilayer of two major phenotypically and functionally distinct cell lineages: luminal epithelial and myoepithelial cells. Mammary luminal epithelia exhibit substantial stereotypical changes with age that merit attention because these cells are the putative cells-of-origin for breast cancers. We hypothesize that effects from aging that impinge upon maintenance of lineage fidelity increase susceptibility to cancer initiation. We generated and analyzed transcriptomes from primary luminal epithelial and myoepithelial cells from younger <30 (y)ears old and older >55y women. In addition to age-dependent directional changes in gene expression, we observed increased transcriptional variance with age that contributed to genome-wide loss of lineage fidelity. Age-dependent variant responses were common to both lineages, whereas directional changes were almost exclusively detected in luminal epithelia and involved altered regulation of chromatin and genome organizers such as SATB1. Epithelial expression of gap junction protein GJB6 increased with age, and modulation of GJB6 expression in heterochronous co-cultures revealed that it provided a communication conduit from myoepithelial cells that drove directional change in luminal cells. Age-dependent luminal transcriptomes comprised a prominent signal that could be detected in bulk tissue during aging and transition into cancers. A machine learning classifier based on luminal-specific aging distinguished normal from cancer tissue and was highly predictive of breast cancer subtype. We speculate that luminal epithelia are the ultimate site of integration of the variant responses to aging in their surrounding tissue, and that their emergent phenotype both endows cells with the ability to become cancer-cells-of-origin and represents a biosensor that presages cancer susceptibility.
