A prostanoid receptor EP4 agonist enhances ectopic bone formation induced by recombinant human bone morphogenetic protein-2

Biochem Biophys Res Commun. 2004 Jun 4;318(3):704-9. doi: 10.1016/j.bbrc.2004.04.080.

Abstract

The anabolic effects of prostaglandin E(2) on bone are effected through the activation of EP4, a G protein-coupled receptor. In the present study, we examined the effects of a prostanoid receptor-selective agonist (ONO-4819) in an experimental system of ectopic bone formation using recombinant human bone morphogenetic protein-2 (rhBMP-2). Collagen pellets containing rhBMP-2 were implanted onto the back muscles of mice and then treated with ONO-4819 administered every 8 h by subcutaneous injection. The ossicles elicited ectopically by rhBMP-2 in mice treated with 30 microg/kg ONO-4819 were significantly larger in size and had a higher bone mineral density and bone mineral content when compared to the controls. We also noted that the anabolic effect of ONO-4819 was seen only in the early phase of the rhBMP-2-induced bone-forming process. These experimental results indicate that the EP4 receptor agonist enhances the rhBMP-2-induced bone formation through a selective effect on early stage mesenchymal cells, which in turn may result in increased responsiveness of the host animals to rhBMP-2.

Publication types

  • Comparative Study

MeSH terms

  • Absorbable Implants
  • Absorptiometry, Photon / methods
  • Alkaline Phosphatase / metabolism
  • Animals
  • Body Weight / drug effects
  • Bone Density / drug effects
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / pharmacology*
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / metabolism*
  • Bone and Bones / ultrastructure
  • Collagen
  • Dose-Response Relationship, Drug
  • Drug Carriers
  • Heptanoates / pharmacology*
  • Humans
  • Male
  • Mice
  • Mice, Inbred ICR
  • Osteocalcin / blood
  • Osteogenesis / drug effects*
  • Receptors, Prostaglandin E / agonists*
  • Receptors, Prostaglandin E, EP4 Subtype
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • Transforming Growth Factor beta*

Substances

  • BMP2 protein, human
  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • Drug Carriers
  • Heptanoates
  • ONO4819
  • PTGER4 protein, human
  • Ptger4 protein, mouse
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP4 Subtype
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • recombinant human bone morphogenetic protein-2
  • Osteocalcin
  • Collagen
  • Alkaline Phosphatase