CB2 cannabinoid receptor targets mitogenic Gi protein-cyclin D1 axis in osteoblasts

Orr Ofek, Malka Attar-Namdar, Vardit Kram, Mona Dvir-Ginzberg, Raphael Mechoulam, Andreas Zimmer, Baruch Frenkel, Esther Shohami, Itai Bab*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

CB2 is a Gi protein-coupled receptor activated by endo- and phytocannabinoids, thus inhibiting stimulated adenylyl cyclase activity. CB2 is expressed in bone cells and Cb2 null mice show a marked age-related bone loss. CB2-specific agonists both attenuate and rescue ovariectomy-induced bone loss. Activation of CB2 stimulates osteoblast proliferation and bone marrow derived colony-forming units osteoblastic. Here we show that selective and nonselective CB2 agonists are mitogenic in MC3T3 E1 and newborn mouse calvarial osteoblastic cultures. The CB2 mitogenic signaling depends critically on the stimulation of Erk1/2 phosphorylation and de novo synthesis of MAP kinase-activated protein kinase 2 (Mapkapk2) mRNA and protein. Further downstream, CB2 activation enhances CREB transcriptional activity and cyclin D1 mRNA expression. The CB2-induced stimulation of CREB and cyclin D1 is inhibitable by pertussis toxin, the MEK-Erk1/2 inhibitors PD098059 and U0126, and Mapkapk2 siRNA. These data demonstrate that in osteoblasts CB2 targets a Gi protein-cyclin D1 mitogenic axis. Erk1/2 phosphorylation and Mapkapk2 protein synthesis are critical intermediates in this axis.

Original languageAmerican English
Pages (from-to)308-316
Number of pages9
JournalJournal of Bone and Mineral Research
Volume26
Issue number2
DOIs
StatePublished - Feb 2011

Keywords

  • CB2 CANNABINOID RECEPTOR
  • CREB
  • CYCLIN D1
  • MAP KINASE
  • MAPKAPK2
  • MITOGENIC SIGNALING
  • OSTEOBLAST

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