title: Bone Cell-autonomous Contribution of Type 2 Cannabinoid Receptor to Breast Cancer-induced Osteolysis.
abstract: The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumor growth, bone remodeling, and bone pain. However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here we found that the CB2-selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micromolar concentrations. Under conditions in which these ligands are used at the nanomolar range, HU308 and JWH133 enhanced human and mouse breast cancer cell-induced osteoclastogenesis and exacerbated osteolysis, and these effects were attenuated in cultures obtained from CB2-deficient mice or in the presence of a CB2 receptor blocker. HU308 and JWH133 had no effects on osteoblast growth or differentiation in the presence of conditioned medium from breast cancer cells, but under these circumstances both agents enhanced parathyroid hormone-induced osteoblast differentiation and the ability to support osteoclast formation. Mechanistic studies in osteoclast precursors and osteoblasts showed that JWH133 and HU308 induced PI3K/AKT activity in a CB2-dependent manner, and these effects were enhanced in the presence of osteolytic and osteoblastic factors such as RANKL (receptor activator of NFκB ligand) and parathyroid hormone. When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands depending upon cell type and concentration used. We, therefore, conclude that both CB2-selective activation and antagonism have potential efficacy in cancer-associated bone disease, but further studies are warranted and ongoing.
authors.affiliation: Bone and Cancer Group, Edinburgh Cancer Research Centre, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom, Rheumatology and Bone Diseases Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom, and.
authors.forename: Antonia
authors.initials: A
authors.lastname: Sophocleous
authors.affiliation: Bone and Cancer Group, Edinburgh Cancer Research Centre, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom, From the Academic Unit of Bone Biology, Mellanby Centre for Bone Research, Department of Human Metabolism, Medical School, Beech Hill Road, Sheffield S10 2RX, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marino
authors.affiliation: Bone and Cancer Group, Edinburgh Cancer Research Centre, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom, Rheumatology and Bone Diseases Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom, and.
authors.forename: John G
authors.initials: JG
authors.lastname: Logan
authors.affiliation: Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mollat
authors.affiliation: Rheumatology and Bone Diseases Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom, and.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.affiliation: Bone and Cancer Group, Edinburgh Cancer Research Centre, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom, From the Academic Unit of Bone Biology, Mellanby Centre for Bone Research, Department of Human Metabolism, Medical School, Beech Hill Road, Sheffield S10 2RX, United Kingdom, aymen.idris@sheffield.ac.uk.
authors.forename: Aymen I
authors.initials: AI
authors.lastname: Idris
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002186:Cannabinoids / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis; D010281:Parathyroid Hormone / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002186:Cannabinoids; D017077:Culture Media, Conditioned; D010281:Parathyroid Hormone; D053245:RANK Ligand; D043885:Receptor, Cannabinoid, CB2; C402416:HU 308; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC
keywords: Akt PKB; G protein-coupled receptor (GPCR); bone; cannabinoid receptor; osteoblast; osteoclast; osteolysis