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

Wolfgang Schuehly, Juan Manuel Viveros Paredes, Jonas Kleyer, Antje Huefner, Sharon Anavi-Goffer, Stefan Raduner, Karl-Heinz Altmann, Jürg Gertsch* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

The 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.
Original languageEnglish
Pages (from-to)1053-1064
Number of pages12
JournalChemistry & Biology
Volume18
Issue number8
Early online date25 Aug 2011
DOIs
Publication statusPublished - 26 Aug 2011

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Cannabinoid Receptor CB2
Osteogenesis
Macrophages
RANK Ligand
Calcium
Endocannabinoids
Lignans
Osteoclasts
Chemotaxis
Scaffolds
Libraries
Inhibition (Psychology)
diphenyl
Ligands
Derivatives

Cite this

Mechanisms of Osteoclastogenesis Inhibition by a Novel Class of Biphenyl-Type Cannabinoid CB2 Receptor Inverse Agonists. / Schuehly, Wolfgang; Paredes, Juan Manuel Viveros; Kleyer, Jonas; Huefner, Antje; Anavi-Goffer, Sharon; Raduner, Stefan; Altmann, Karl-Heinz; Gertsch, Jürg (Corresponding Author).

In: Chemistry & Biology, Vol. 18, No. 8, 26.08.2011, p. 1053-1064.

Research output: Contribution to journalArticle

Schuehly, Wolfgang ; Paredes, Juan Manuel Viveros ; Kleyer, Jonas ; Huefner, Antje ; Anavi-Goffer, Sharon ; Raduner, Stefan ; Altmann, Karl-Heinz ; Gertsch, Jürg. / Mechanisms of Osteoclastogenesis Inhibition by a Novel Class of Biphenyl-Type Cannabinoid CB2 Receptor Inverse Agonists. In: Chemistry & Biology. 2011 ; Vol. 18, No. 8. pp. 1053-1064.
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abstract = "The 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.",
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N2 - The 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.

AB - The 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.

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