Age-related regulation of bone formation by the sympathetic cannabinoid CB1 receptor

Saif Deis, Raj Kamal Srivastava, Inigo Ruiz de Azua, Laura Bindila, Saja Baraghithy, Beat Lutz, Itai Bab, Joseph Tam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


The endocannabinoid (eCB) system, including its receptors, ligands, and their metabolizing enzymes, plays an important role in bone physiology. Skeletal cannabinoid type 1 (CB1) receptor signaling transmits retrograde signals that restrain norepinephrine (NE) release, thus transiently stimulating bone formation following an acute challenge, suggesting a feedback circuit between sympathetic nerve terminals and osteoblasts. To assess the effect of chronic in vivo occurrence of this circuit, we characterized the skeletal phenotype of mice with a conditional deletion of the CB1 receptor in adrenergic/noradrenergic cells, including sympathetic nerves. Whereas the deletion of the CB1 receptor did not affect bone mass accrual in the distal femoral metaphysis and in vertebral bodies of young, 12-week-old mice, it substantially increased bone mass in aged, 35-week-old mutant mice as compared to wild-type controls. Contrary to our expectations, specific deficiency of the CB1 receptor in sympathetic neurons led to a markedly increased bone mass phenotype, associated with an enhanced bone formation rate and reduced osteoclastogenesis. Mechanistically, the reduced skeletal eCB ‘tone’ in the null mice did not reflect in increased sympathetic tone and reduced bone formation, suggesting that constitutive genetic inactivation of sympathetic CB1 receptor disrupts the negative feedback loop between eCBs and NE signaling in bone.

Original languageAmerican English
Pages (from-to)34-42
Number of pages9
StatePublished - Mar 2018

Bibliographical note

Funding Information:
This work was supported by the German-Israeli Foundation (GIF) grant (# 1118-116.1/2010 ) to I.B. and B.L, and the ABISH-FRENKEL FOUNDATION grant (#15/H6 ) to J.T. The authors declare no competing financial interests. We are grateful to Ms. Yael Soae for her technical assistance with histology analysis.

Publisher Copyright:
© 2017 Elsevier Inc.


  • Bone remodeling
  • CB1 receptor
  • Endocannabinoids
  • Neuropeptide Y
  • Norepinephrine


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