Mechanisms of Osteoclastogenesis Inhibition by a Novel Class of Biphenyl-Type Cannabinoid CB2 Receptor Inverse Agonists

SummaryThe cannabinoid CB2 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 CB2 receptor-selective antiosteoclastogenic lead structure (Ki < 50 nM). Intriguingly, MH triggers a simultaneous Gi inverse agonist response and a strong CB2 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 CB2 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 CB2 receptor-selective scaffold that exhibits a novel type of functional heterogeneity.

Graphical AbstractFigure optionsDownload high-quality image (355 K)Download as PowerPoint slideHighlights
► Methylhonokiol from the ancient plant genus Magnolia is a CB2 receptor-selective lead structure
► The biphenyl scaffold exerts a novel type of mixed inverse agonist and agonist effect
► CB2 receptor inverse agonists inhibit osteoclastogenesis by inhibition of chemotaxis via cAMP
► Endocannabinoids stimulate osteoclast syncytium formation in a cAMP-dependent manner