title: Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB(2) receptor inverse agonists.
abstract: The cannabinoid CB(2) receptor is known to modulate osteoclast function by poorly understood mechanisms. Here, we report that the natural biphenyl neolignan 4'-O-methylhonokiol (MH) is a CB(2) receptor-selective antiosteoclastogenic lead structure (K(i) < 50 nM). Intriguingly, MH triggers a simultaneous G(i) inverse agonist response and a strong CB(2) receptor-dependent increase in intracellular calcium. The most active inverse agonists from a library of MH derivatives inhibited osteoclastogenesis in RANK ligand-stimulated RAW264.7 cells and primary human macrophages. Moreover, these ligands potently inhibited the osteoclastogenic action of endocannabinoids. Our data show that CB(2) receptor-mediated cAMP formation, but not intracellular calcium, is crucially involved in the regulation of osteoclastogenesis, primarily by inhibiting macrophage chemotaxis and TNF-α expression. MH is an easily accessible CB(2) receptor-selective scaffold that exhibits a novel type of functional heterogeneity.
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schuehly
authors.forename: Juan Manuel Viveros
authors.initials: JM
authors.lastname: Paredes
authors.forename: Jonas
authors.initials: J
authors.lastname: Kleyer
authors.forename: Antje
authors.initials: A
authors.lastname: Huefner
authors.forename: Sharon
authors.initials: S
authors.lastname: Anavi-Goffer
authors.forename: Stefan
authors.initials: S
authors.lastname: Raduner
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002460:Cell Line; D002464:Cell Migration Inhibition / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D017705:Lignans / Q000737:chemistry* / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D010944:Plants / Q000737:chemistry; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D002118:Calcium; D063385:Cannabinoid Receptor Modulators; D000242:Cyclic AMP; D017705:Lignans; D010936:Plant Extracts; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; C542058:4-O-methylhonokiol; C010574:biphenyl