Impaired bone resorption to prostaglandin E-2 in prostaglandin E receptor EP4-knockout mice

Prostaglandin E-2 (PGE(2)) acts as a potent stimulator of bone resorption. In this study, we first clarified in normal ddy mice the involvement of pro tein kinase A and induction of matrix metalloproteinases (MMPs) in PGE(2)-i nduced bone resorption, and then identified PGE receptor subtype(s) mediati ng this PGE(2) action using mice lacking each subtype (EP1, EP2, EP3, and E P4) of PGE receptor. In calvarial culture obtained from normal ddy mice, bo th PGE(2) and dibutyryl cyclic AMP (Bt(2)cAMP) stimulated bone resorption a nd induced MMPs including MMP-2 and MMP-13. Addition of an inhibitor of pro tein kinase A, H89, or an inhibitor of MMPs, BB94, significantly suppressed bone-resorbing activity induced by PGE(2). In calvarial culture from EP1-, EP2-, and EP3-knockout mice, PGE(2) stimulated bone resorption to an exten t similar to that found in calvaria from the wild-type mice. On the other h and, a marked reduction in bone resorption to PGE(2) was found in the calva rial culture from EP4-knockout mice. The impaired bone resorption to PGE(2) was also detected in long bone cultures from EP4-knockout mice. Bt(2)cAMP greatly stimulated bone resorption similarly in both wild-type and EP4-knoc kout mice. Induction of MMP-2 and MMP-13 by PGE(2) was greatly impaired in calvarial culture from EP4-knockout mice, but Bt(2)cAMP stimulated MMPs ind uction similarly in the wild-type and EP4-knockout mice. These findings sug gest that PGE(2) stimulates bone resorption by a cAMP-dependent mechanism v ia the EP4 receptor.