title: Effect of a selective agonist for prostaglandin E receptor subtype EP4 (ONO-4819) on the cortical bone response to mechanical loading.
abstract: The influence of a selective agonist for prostaglandin E receptor subtype EP4 (ONO-4819) on the bone response to mechanical loading was evaluated. Six-month-old female Wistar rats were used and assigned to three groups (n = 12/group): Vehicle administration (EP4-V), low-dose ONO-4819 administration (EP4-L, 3 microg/kg BW), and high-dose ONO-4819 administration (EP4-H, 30 microg/kg BW). ONO-4819 was subcutaneously injected in the back twice a day for 3 weeks. Loads on the right tibia at 39.4 N for 36 cycles at 2 Hz were applied in vivo by 4-point bending every other day for 3 weeks. Whole-body bone mineral content showed a significant difference between EP4-V and EP4-H (P < 0.05). Bone mineral density (BMD) of the total and regional tibia (the region with maximal bending at the central diaphysis) was higher in EP4-H than EP4-V, showing a significant effect of loading (P < 0.001) and ONO-4819 (P < 0.05). BMD of the total femur was higher in EP4-H than EP4-V (P < 0.01) and that of the distal femur was higher in EP4-H than EP4-V (P < 0.001). Histomorphometry of the cortical bone showed that loading increased formation surface (FS/BS), mineral appositional rate (MAR), and bone formation rate (BFR/BS) significantly at the lateral periosteal surface (P < 0.001); however, the effect of ONO-4819 was not significant. At the medial periosteal surface, loading increased the three parameters (P < 0.001) and ONO-4819 increased FS/BS (P < 0.001) and MAR (P < 0.05) significantly. At the endocortical surface, the effects of both loading and ONO-4819 were significant on all three parameters (for loading; FS/BS P < 0.01, MAR P < 0.05, BFR/BS P < 0.03, for ONO-4819 all P < 0.001). It was concluded that ONO-4819 increased cortical bone formation in rats and there was an additive effect on the bone response to external loading by 4-point bending.
authors.affiliation: Rehabilitation Division, Tottori University Hospital, Yonago, Tottori 683-8504, Japan. hagino@grape.med.tottori-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Hagino
authors.forename: M
authors.initials: M
authors.lastname: Kuraoka
authors.forename: Y
authors.initials: Y
authors.lastname: Kameyama
authors.forename: T
authors.initials: T
authors.lastname: Okano
authors.forename: R
authors.initials: R
authors.lastname: Teshima
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects* / Q000502:physiology; D001842:Bone and Bones / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005269:Femur / Q000187:drug effects / Q000502:physiology; D006537:Heptanoates / Q000008:administration & dosage / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000502:physiology; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013314:Stress, Mechanical; D013977:Tibia / Q000187:drug effects / Q000502:physiology; D016474:Weight-Bearing / Q000502:physiology
chemical_list: D006537:Heptanoates; C487764:ONO4819; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype