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Impaired bone resorption to prostaglandin E2 in prostaglandin E receptor EP4-knockout mice. 2000

C Miyaura, and M Inada, and T Suzawa, and Y Sugimoto, and F Ushikubi, and A Ichikawa, and S Narumiya, and T Suda
Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.

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 protein kinase A and induction of matrix metalloproteinases (MMPs) in PGE(2)-induced bone resorption, and then identified PGE receptor subtype(s) mediating this PGE(2) action using mice lacking each subtype (EP1, EP2, EP3, and EP4) of PGE receptor. In calvarial culture obtained from normal ddy mice, both PGE(2) and dibutyryl cyclic AMP (Bt(2)cAMP) stimulated bone resorption and induced MMPs including MMP-2 and MMP-13. Addition of an inhibitor of protein 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 extent similar to that found in calvaria from the wild-type mice. On the other hand, a marked reduction in bone resorption to PGE(2) was found in the calvarial 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-knockout 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 induction similarly in the wild-type and EP4-knockout mice. These findings suggest that PGE(2) stimulates bone resorption by a cAMP-dependent mechanism via the EP4 receptor.

UI MeSH Term Description Entries
D001862 Bone Resorption Bone loss due to osteoclastic activity. Bone Loss, Osteoclastic,Osteoclastic Bone Loss,Bone Losses, Osteoclastic,Bone Resorptions,Loss, Osteoclastic Bone,Losses, Osteoclastic Bone,Osteoclastic Bone Losses,Resorption, Bone,Resorptions, Bone
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D003994 Bucladesine A cyclic nucleotide derivative that mimics the action of endogenous CYCLIC AMP and is capable of permeating the cell membrane. It has vasodilator properties and is used as a cardiac stimulant. (From Merck Index, 11th ed) Dibutyryl Adenosine-3',5'-Monophosphate,Dibutyryl Cyclic AMP,(But)(2) cAMP,Bucladesine, Barium (1:1) Salt,Bucladesine, Disodium Salt,Bucladesine, Monosodium Salt,Bucladesine, Sodium Salt,DBcAMP,Dibutyryl Adenosine 3,5 Monophosphate,N',O'-Dibutyryl-cAMP,N(6),0(2')-Dibutyryl Cyclic AMP,AMP, Dibutyryl Cyclic,Adenosine-3',5'-Monophosphate, Dibutyryl,Cyclic AMP, Dibutyryl,Dibutyryl Adenosine 3',5' Monophosphate,Disodium Salt Bucladesine,Monosodium Salt Bucladesine,N',O' Dibutyryl cAMP,Sodium Salt Bucladesine
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D005838 Genotype The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS. Genogroup,Genogroups,Genotypes
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000831 Animals, Newborn Refers to animals in the period of time just after birth. Animals, Neonatal,Animal, Neonatal,Animal, Newborn,Neonatal Animal,Neonatal Animals,Newborn Animal,Newborn Animals
D012886 Skull The SKELETON of the HEAD including the FACIAL BONES and the bones enclosing the BRAIN. Calvaria,Cranium,Calvarium,Skulls
D015152 Blotting, Northern Detection of RNA that has been electrophoretically separated and immobilized by blotting on nitrocellulose or other type of paper or nylon membrane followed by hybridization with labeled NUCLEIC ACID PROBES. Northern Blotting,Blot, Northern,Northern Blot,Blots, Northern,Blottings, Northern,Northern Blots,Northern Blottings
D015153 Blotting, Western Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes. Immunoblotting, Western,Western Blotting,Western Immunoblotting,Blot, Western,Immunoblot, Western,Western Blot,Western Immunoblot,Blots, Western,Blottings, Western,Immunoblots, Western,Immunoblottings, Western,Western Blots,Western Blottings,Western Immunoblots,Western Immunoblottings

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