The endogenous opioid dynorphin is required for normal bone homeostasis in mice

Paul A. Baldock, Frank Driessler, Shu Lin, Iris P. L. Wong, Yanchuan Shi, Ernie Yulyaningsih, Lesley Castillo, Sonia Janmaat, Ronaldo F. Enriquez, Ayse Zengin, Brigitte L. Kieffer, Christoph Schwarzer, John A. Eisman, Amanda Sainsbury, Herbert Herzog

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)


Chronic opiate usage, whether prescribed or illicit, has been associated with changes in bone mass and is a recognized risk factor for the development of osteoporosis; however, the mechanism behind this effect is unknown. Here we show that lack of dynorphin, an endogenous opioid, in mice (Dyn-/-), resulted in a significantly elevated cancellous bone volume associated with greater mineral apposition rate and increased resorption indices. A similar anabolic phenotype was evident in bone of mice lacking dynorphin's cognate receptor, the kappa opioid receptor. Lack of opioid receptor expression in primary osteoblastic cultures and no change in bone cell function after dynorphin agonist treatment in vitro indicates an indirect mode of action. Consistent with a hypothalamic action, central dynorphin signaling induces extracellular signal-regulated kinase (ERK) phosphorylation and c-fos activation of neurons in the arcuate nucleus of the hypothalamus (Arc). Importantly, this signaling also leads to an increase in Arc NPY mRNA expression, a change known to decrease bone formation. Further implicating NPY in the skeletal effects of dynorphin, Dyn-/-/NPY-/- double mutant mice showed comparable increases in bone formation to single mutant mice, suggesting that dynorphin acts upstream of NPY signaling to control bone formation. Thus the dynorphin system, acting via NPY, may represent a pathway by which higher processes including stress, reward/addiction and depression influence skeletal metabolism. Moreover, understanding of these unique interactions may enable modulation of the adverse effects of exogenous opioid treatment without directly affecting analgesic responses.

Original languageEnglish
Pages (from-to)383-394
Number of pages12
Issue number6
Publication statusPublished - Dec 2012
Externally publishedYes


  • Animal models
  • Bone histomorphometry
  • Molecular pathways
  • Neural factors
  • Osteoblasts

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