The role of prostaglandin E receptor subtypes (EP1, EP2, EP3, and EP4) in bone resorption: An analysis using specific agonists for the respective EPs

PGE(2) functions as a potent stimulator of bone resorption. The action of P GE(2) is thought to be mediated by some PGE receptor subtypes present in os teoblastic cells. In this study, we examined the involvement of PGE recepto r subtypes, EP1, EP2, EP3, and EP4, in PGE(2)-induced bone resorption using specific agonists for the respective EPs. In mouse calvaria cultures, EP4 agonist markedly stimulated bone resorption, but its maximal stimulation wa s less than that induced by PGE(2). EP2 agonist also stimulated bone resorp tion, but only slightly. EP1 and EP3 agonists did not stimulate it at all. RT-PCR showed that osteoblastic cells isolated from newborn mouse calvaria expressed all of the EPs messenger RNA (mRNA). Both EP2 agonist and EP4 ago nist induced cAMP production and the expression of osteoclast differentiati on factor (ODF) mnNA in osteoblastic cells. Simultaneous addition of EP2 an d EP4 agonists cooperatively induced cAMP production and ODF mRNA expressio n. In mouse bone marrow cultures, EP2 and EP3 agonists moderately induced o steoclast formation, but the simultaneous addition of the two agonists coop eratively induced it, similar to that by PGE(2). In calvaria culture from E P4 knockout mice, a marked reduction in bone resorption to PGE(2) was found . In EP3 knockout mice, EP4 agonist failed to induce bone resorption, but E P2 agonist slightly, but significantly, induced bone resorption. These find ings suggest that PGE(2) stimulates bone resorption by a mechanism involvin g cAMP and ODF, which is mediated mainly by EP4 and partially by EP2.