Prostaglandin receptor EP4 mediates the bone anabolic effects of PGE(2)

Prostagtandin (PG) E-2 is a potent inducer of cortical and trabecular bone formation in humans and animals. Although the bone anabolic action of PGE(2 ) is well documented, the cellular and molecular mechanisms that mediate th is effect remain unclear. This study was undertaken to examine the effect o f pharmacological inactivation of the prostanoid receptor EP4, one of the P GE(2) receptors, on PGE(2)-induced boneformation in vive. We first determin ed the ability of EP(4)A, an EP4-selective ligand, to act as an antagonist. PGE(2) increases intracellular cAMP and suppresses apoptosis in the RP-1 p eriosteal cell line. Both effects were reversed by EP(4)A, suggesting that EP(4)A acts as an EP4 antagonist in the cells at concentrations consistent with its in vitro binding to EP4. We then examined the effect of EP4 on bon e formation induced by PGE(2) in young rats. Five- to 6-week-old rats were treated with PGE(2) (6 mg/kg/day) in the presence or absence of EP(4)A (10 mg/kg/day) for 12 days. We found that treatment with EP(4)A suppresses the increase in trabecular bone volume induced by PGE(2). This effect is accomp anied by a suppression of bone formation indices: serum osteocalcin, extent of labeled surface, and extent of trabecular number, suggesting that the r eduction in bone volume is due most likely to decreased bone formation. The pharmacological evidence presented here provides strong support for the hy pothesis that the bone anabolic effect of PGE(2) in rats is mediated by the EP4 receptor.