Reduced bone turnover in mice lacking the P2Y13 receptor of ADP

Mol Endocrinol. 2012 Jan;26(1):142-52. doi: 10.1210/me.2011-1083. Epub 2011 Nov 22.


Osteoporosis is a condition of excessive and uncoupled bone turnover, in which osteoclastic resorption exceeds osteoblastic bone formation, resulting in an overall net bone loss, bone fragility, and morbidity. Although numerous treatments have been developed to inhibit bone loss by blocking osteoclastic bone resorption, understanding of the mechanisms behind bone loss is incomplete. The purinergic signaling system is emerging to be a pivotal regulator of bone homeostasis, and extracellular ADP has previously been shown to be a powerful osteolytic agent in vitro. We report here that deletion of the P2Y(13) receptor, a G protein-coupled receptor for extracellular ADP, leads to a 40% reduction in trabecular bone mass, 50% reduction in osteoblast and osteoclast numbers in vivo, as well as activity in vitro, and an overall 50% reduction in the rate of bone remodeling in mice in vivo. Down-regulation of RhoA/ROCK I signaling and a reduced ratio of receptor activator of nuclear factor κB ligand/osteoprotegerin observed in osteoblasts from P2Y(13)R(-/-) mice might explain this bone phenotype. Furthermore, because one of the main causes of osteoporosis in older women is lack of estrogen, we examined the effect of ovariectomy of the P2Y(13)R(-/-) mice and found them to be protected from ovariectomy-induced bone loss by up to 65%. These data confirm a role of purinergic ADP signaling in the skeleton, whereby deletion of the P2Y(13) receptor leads to reduced bone turnover rates, which provide a protective advantage in conditions of accelerated bone turnover such as oestrogen deficiency-induced osteoporosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Remodeling*
  • Bone Resorption*
  • Bone and Bones / metabolism
  • Cells, Cultured
  • Estrogens / blood
  • Female
  • Mice
  • Mice, Knockout
  • NF-kappa B / biosynthesis
  • Osteoblasts / metabolism
  • Osteoblasts / physiology
  • Osteoclasts / metabolism
  • Osteoclasts / physiology
  • Osteoporosis / genetics
  • Osteoporosis / metabolism
  • Osteoporosis / prevention & control
  • Osteoprotegerin / biosynthesis
  • Ovariectomy / adverse effects
  • Receptors, Purinergic P2 / deficiency
  • Receptors, Purinergic P2 / genetics*
  • Receptors, Purinergic P2 / physiology*
  • Signal Transduction
  • rho GTP-Binding Proteins / biosynthesis
  • rho-Associated Kinases / biosynthesis
  • rhoA GTP-Binding Protein


  • Estrogens
  • NF-kappa B
  • Osteoprotegerin
  • P2ry13 protein, mouse
  • Receptors, Purinergic P2
  • rho-Associated Kinases
  • RhoA protein, mouse
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein