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

doi:10.1016/j.chembiol.2011.05.012

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

Applied Medicine

Research output: Contribution to journal › Article › peer-review

64 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 language	English
Pages (from-to)	1053-1064
Number of pages	12
Journal	Chemistry & Biology
Volume	18
Issue number	8
Early online date	25 Aug 2011
DOIs	https://doi.org/10.1016/j.chembiol.2011.05.012
Publication status	Published - 26 Aug 2011

Bibliographical note

This work was supported by the Swiss National Science Foundation (SNSF) grant 31003A_120672. We thank Bernhard Faller and Jacques Hamon from Novartis Institutes for BioMedical Research, Switzerland, for performing the profiling experiment. We thank Maria Feher for isolation of blood-derived monocytes. We express our gratitude to Marketa Bernaskova (FWF grant P21241) for the synthesis of several honokiol derivatives. Thanks are due to Andreas Leitner and Elke Prettner for recording IR and UV spectra of synthesized compounds.

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

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.",

author = "Wolfgang Schuehly and Paredes, \{Juan Manuel Viveros\} and Jonas Kleyer and Antje Huefner and Sharon Anavi-Goffer and Stefan Raduner and Karl-Heinz Altmann and J{\"u}rg Gertsch",

note = "This work was supported by the Swiss National Science Foundation (SNSF) grant 31003A\_120672. We thank Bernhard Faller and Jacques Hamon from Novartis Institutes for BioMedical Research, Switzerland, for performing the profiling experiment. We thank Maria Feher for isolation of blood-derived monocytes. We express our gratitude to Marketa Bernaskova (FWF grant P21241) for the synthesis of several honokiol derivatives. Thanks are due to Andreas Leitner and Elke Prettner for recording IR and UV spectra of synthesized compounds.",

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doi = "10.1016/j.chembiol.2011.05.012",

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AU - Schuehly, Wolfgang

AU - Paredes, Juan Manuel Viveros

AU - Kleyer, Jonas

AU - Huefner, Antje

AU - Anavi-Goffer, Sharon

AU - Raduner, Stefan

AU - Altmann, Karl-Heinz

AU - Gertsch, Jürg

N1 - This work was supported by the Swiss National Science Foundation (SNSF) grant 31003A_120672. We thank Bernhard Faller and Jacques Hamon from Novartis Institutes for BioMedical Research, Switzerland, for performing the profiling experiment. We thank Maria Feher for isolation of blood-derived monocytes. We express our gratitude to Marketa Bernaskova (FWF grant P21241) for the synthesis of several honokiol derivatives. Thanks are due to Andreas Leitner and Elke Prettner for recording IR and UV spectra of synthesized compounds.

PY - 2011/8/26

Y1 - 2011/8/26

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.

U2 - 10.1016/j.chembiol.2011.05.012

DO - 10.1016/j.chembiol.2011.05.012

M3 - Article

C2 - 21867920

SN - 1074-5521

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SP - 1053

EP - 1064

JO - Chemistry & Biology

JF - Chemistry & Biology

IS - 8

ER -

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

Abstract

Bibliographical note

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