Prostaglandin Receptor EP4 Mediates the Bone Anabolic Effects of PGE2

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Vol. 60, Issue 1, 36-41, July 2001

Prostaglandin Receptor EP₄ Mediates the Bone Anabolic Effects of PGE₂

M. Machwate, S. Harada, C. T. Leu, G. Seedor, M. Labelle, M. Gallant, S. Hutchins, N. Lachance, N. Sawyer, D. Slipetz, K. M. Metters, S. B. Rodan, R. Young, and G. A. Rodan

Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, Pennsylvania (M.M., S.H., C.T.L., G.S., S.B.R., G.A.R.); and Merck Frosst, Kirkland, Quebec, Canada (M.L., M.G., S.H., N.L., N.S., D.S., K.M.M., R.Y.)

Prostaglandin (PG) E₂ is a potent inducer of cortical and trabecular bone formation in humans and animals. Although the boneanabolic action of PGE₂ is well documented, the cellular and molecularmechanisms that mediate this effect remain unclear. This studywas undertaken to examine the effect of pharmacological inactivationof the prostanoid receptor EP₄, one of the PGE₂ receptors, onPGE₂-induced bone formation in vivo. We first determined the abilityof EP₄A, an EP₄-selective ligand, to act as an antagonist. PGE₂increases intracellular cAMP and suppresses apoptosis in the RP-1periosteal cell line. Both effects were reversed by EP₄A, suggestingthat EP₄A acts as an EP₄ antagonist in the cells at concentrationsconsistent with its in vitro binding to EP₄. We then examinedthe effect of EP₄ on bone formation induced by PGE₂ in young rats.Five- to 6-week-old rats were treated with PGE₂ (6 mg/kg/day)in the presence or absence of EP₄A (10 mg/kg/day) for 12 days.We found that treatment with EP₄A suppresses the increase in trabecularbone volume induced by PGE₂. This effect is accompanied by a suppressionof bone formation indices: serum osteocalcin, extent of labeledsurface, and extent of trabecular number, suggesting that thereduction in bone volume is due most likely to decreased boneformation. The pharmacological evidence presented here providesstrong support for the hypothesis that the bone anabolic effectof PGE₂ in rats is mediated by the EP₄receptor.

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