CoChat
Sign Up
Cited by 356Bone Metabolism and DiseasesCannabis and Cannabinoid ResearchBone health and osteoporosis research

Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors

Open access
Idris, Aymen I, van 't Hof, Robert J, Greig, Iain R, Ridge, Susan A, Baker, David, Ross, Ruth A, Ralston, Stuart H·2005·Nature Medicine
DOI 10.1038/nm1255PMC PMC1430341
Open this paper in CoChat — free account

Abstract

Accelerated osteoclastic bone resorption has a central role in the pathogenesis of osteoporosis and other bone diseases. Identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and to the development of new treatments. Here we show that mice with inactivation of cannabinoid type 1 (CB1) receptors have increased bone mass and are protected from ovariectomy-induced bone loss. Pharmacological antagonists of CB1 and CB2 receptors prevented ovariectomy-induced bone loss in vivo and caused osteoclast inhibition in vitro by promoting osteoclast apoptosis and inhibiting production of several osteoclast survival factors. These studies show that the CB1 receptor has a role in the regulation of bone mass and ovariectomy-induced bone loss and that CB1- and CB2-selective cannabinoid receptor antagonists are a new class of osteoclast inhibitors that may be of value in the treatment of osteoporosis and other bone diseases.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/nm1255

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Increased β-adrenergic activity can reduce bone mass.

    “Increased β-adrenergic activity can decrease bone mass, but other neural pathways may be involved (104, 105).”

    From Pathogenesis of osteoporosis: concepts, conflicts, and prospects (2005) · cites this paper as [104]

    The Introduction (page unavailable) says neuroendocrine pathways and neurotransmitters regulate bone remodelling, but does not identify β-adrenergic activity. The Results and Discussion (pages unavailable) address cannabinoid receptors and bone mass; searches for β-adrenergic activity and sympathetic signalling found no passage supporting the specific claim. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 25 · Cited by 356

Research works printed but not linked: 21

  1. [1]Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289:1504–1508. doi: 10.1126/science.289.5484.1504. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  2. [2]Helfrich MH. Osteoclast diseases. MicroscResTech. 2003;61:514–532. doi: 10.1002/jemt.10375. [DOI] [PubMed] [Google Scholar] · DOI
  3. [3]Rodan GA, Martin TJ. Therapeutic approaches to bone diseases. Science. 2000;289:1508–1514. doi: 10.1126/science.289.5484.1508. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  4. [4]Khosla S. Minireview: The OPG/RANKL/RANK System. Endocrinology. 2001;142:5050–5055. doi: 10.1210/endo.142.12.8536. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  5. [5]Baldock PA, et al. Hypothalamic Y2 receptors regulate bone formation. JClinInvest. 2002;109:915–921. doi: 10.1172/JCI14588. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  6. [6]Skerry TM, Genever PG. Glutamate signalling in non–neuronal tissues. Trends PharmacolSci. 2001;22:174–181. doi: 10.1016/s0165-6147(00)01642-4. [DOI] [PubMed] [Google Scholar] van’t Hof RJ, Macphee J, Libouban H, Helfrich MH, Ralston SH. Regulation of bone mass and bone turnover by neuronal nitric oxide synthase. Endocrinology. 2004;145:5068–5074. doi: 10.1210/en.2004-0205. [DOI] [PubMed] [Google Scholar] · DOI
  7. [8]Ducy P, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000;100:197–207. doi: 10.1016/s0092-8674(00)81558-5. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  8. [10]Pertwee RG, Ross RA. Cannabinoid receptors and their ligands. Prostaglandins LeukotEssentFatty Acids. 2002;66:101–121. doi: 10.1054/plef.2001.0341. [DOI] [PubMed] [Google Scholar] · DOI
  9. [11]Ravinet TC, et al. Anti–obesity effect of SR141716, a CB1 receptor antagonist, in diet–induced obese mice. AmJ Physiol RegulIntegrComp Physiol. 2003;284:R345–R353. doi: 10.1152/ajpregu.00545.2002. [DOI] [PubMed] [Google Scholar] · DOI
  10. [12]Shearman LP, et al. Antidepressant–like and anorectic effects of the cannabinoid CB1 receptor inverse agonist AM251 in mice. BehavPharmacol. 2003;14:573–582. doi: 10.1097/00008877-200312000-00001. [DOI] [PubMed] [Google Scholar] · DOI
  11. [13]Hildebrandt AL, Kelly–Sullivan DM, Black SC. Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet–induced obese mice. EurJPharmacol. 2003;462:125–132. doi: 10.1016/s0014-2999(03)01343-8. [DOI] [PubMed] [Google Scholar] · DOI
  12. [14]Takayanagi H, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. DevCell. 2002;3:889–901. doi: 10.1016/s1534-5807(02)00369-6. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  13. [15]David JP, Sabapathy K, Hoffmann O, Idarraga MH, Wagner EF. JNK1 modulates osteoclastogenesis through both c–Jun phosphorylation–dependent and –independent mechanisms. J Cell Sci. 2002;115:4317–4325. doi: 10.1242/jcs.00082. [DOI] [PubMed] [Google Scholar] · DOI
  14. [16]Grigoriadis AE, et al. c–Fos: a key regulator of osteoclast–macrophage lineage determination and bone remodeling. Science. 1994;266:443–448. doi: 10.1126/science.7939685. [DOI] [PubMed] [Google Scholar] · DOI
  15. [17]Howlett AC, et al. International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors. PharmacolRev. 2002;54:161–202. doi: 10.1124/pr.54.2.161. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  16. [18]Takahashi, N., N. Udagawa, S. Tanaka, T. Suda. Generating murine osteoclasts from bone marrow. Helfrich, M. H. and Ralston, S. H. Bone Research Protocols. 129–144 (2003). Totowa, New Jersey, Humana Press. Methods in Molecular Medicine. Walker, J. M. [DOI] [PubMed]
  17. [19]Coxon FP, et al. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI–298. JBone MinerRes. 2000;15:1467–1476. doi: 10.1359/jbmr.2000.15.8.1467. [DOI] [PubMed] [Google Scholar] van’t Hof RJ, et al. Identification of biphenylcarboxylic acid derivatives as a novel class of bone resorption inhibitors. JBone MinerRes. 2004;19:1651–1660. doi: 10.1359/jbmr.2004.19.10.1651. [DOI] [PubMed] [Google Scholar] · DOI
  18. [21]Howlett AC, Song C, Berglund BA, Wilken GH, Pigg JJ. Characterization of CB1 cannabinoid receptors using receptor peptide fragments and site–directed antibodies. MolPharmacol. 1998;53:504–510. doi: 10.1124/mol.53.3.504. [DOI] [PubMed] [Google Scholar] · DOI
  19. [22]Casanova ML, et al. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J ClinInvest. 2003;111:43–50. doi: 10.1172/JCI16116. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  20. [23]Pryce G, et al. Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain. 2003;126:2191–2202. doi: 10.1093/brain/awg224. [DOI] [PubMed] [Google Scholar] · DOI
  21. [24]Armour KE, et al. Defective bone formation and anabolic responses to exogenous estrogen in mice with targeted disruption of endothelial nitric oxide sythase. Endocrinology. 2001;142:760–766. doi: 10.1210/endo.142.2.7977. [DOI] [PubMed] [Google Scholar] · DOI

Authors
Idris, A. I., van 't Hof, R. J., Greig, I. R., Ridge, S. A., Baker, D., Ross, R. A., & Ralston, S. H.
Affiliations
  • University of Aberdeen (GB)
  • UCL Queen Square Institute of Neurology (GB)
Corresponding author
Ralston, Stuart H
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2005-05-22
Volume
11
Issue
7
Pages
774-779
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm1255
PMC
PMC1430341
OpenAlex
W2165884167
Cited by
356
References
25
Citations by year
2026: 16 · 2025: 5 · 2024: 9 · 2023: 14 · 2022: 19 · 2021: 14 · 2020: 13 · 2019: 16 · 2018: 10 · 2017: 19 · 2016: 12 · 2015: 19 · 2014: 8 · 2013: 14 · 2012: 15
FWCI
10.14
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Funders
  • Multiple Sclerosis Society
  • National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords
cannabinoid receptors, CB1 receptor, CB2 receptor, osteoclasts, bone resorption, bone loss, osteoporosis, ovariectomy, osteoclast apoptosis, cannabinoid receptor antagonists, bone mass regulation
MeSH terms
Animals, Bone and Bones, Bone Resorption, Camphanes, Carrier Proteins, Cells, Cultured, Female, Indoles, Ligands, Membrane Glycoproteins, Mice, Inbred C57BL, Osteoclasts, Ovariectomy, Piperidines, Pyrazoles, Rabbits, Bone Density, Apoptosis, Mice, Knockout, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Mice, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review