Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB(2) receptor inverse agonists

Schuehly, Wolfgang; Paredes, Juan Manuel Viveros; Kleyer, Jonas; Huefner, Antje; Anavi-Goffer, Sharon; Raduner, Stefan; Altmann, Karl-Heinz; Gertsch, Jürg (2011). Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB(2) receptor inverse agonists. Chemistry & biology, 18(8), pp. 1053-64. San Francisco, Calif.: Current Biology Ltd. 10.1016/j.chembiol.2011.05.012

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Gertsch, Jürg

ISSN:

1074-5521

Publisher:

Current Biology Ltd.

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:23

Last Modified:

06 Dec 2013 13:29

Publisher DOI:

10.1016/j.chembiol.2011.05.012

PubMed ID:

21867920

Web of Science ID:

000295203200015

URI:

https://boris.unibe.ch/id/eprint/8155 (FactScience: 213643)

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