title: Association of microsomal prostaglandin E synthase 1 deficiency with impaired fracture healing, but not with bone loss or osteoarthritis, in mouse models of skeletal disorders.
abstract: OBJECTIVE
  Prostaglandin E synthase (PGES) functions as the terminal enzyme in the biosynthesis of prostaglandin E(2) (PGE(2)) and is a potent regulator of bone and cartilage metabolism. Among the 3 isozymes of PGES, microsomal PGES-1 (mPGES-1) is known to play the most critical role in the production of PGE(2) in pathophysiologic events. This study investigated the roles of mPGES-1 under normal physiologic and pathophysiologic conditions in the skeletons of mPGES-1-deficient (mPGES-1(-/-)) mice.
  
  
  METHODS
  Skeletons of mPGES-1(-/-) mice and their wild-type littermates were compared by radiologic and histologic analyses. Four models of skeletal disorders were created: bone loss induced by ovariectomy, bone loss induced by hind limb unloading, osteoarthritis (OA) induced by instability in the knee joint, and bone fracture by osteotomy at the tibial midshaft. Expression of the PGES enzymes was examined by immunohistochemistry and real-time reverse transcription-polymerase chain reaction. The cellular mechanism of fracture healing was examined in ex vivo cultures of costal cartilage chondrocytes.
  
  
  RESULTS
  Microsomal PGES-1(-/-) mice had unaffected skeletal phenotypes under normal physiologic conditions. In the bone fracture model, fracture healing was impaired by the mPGES-1 deficiency, with half of the mice remaining in a non-bone union state even after 21 days; normal fracture healing was restored by adenoviral reintroduction of mPGES-1. The other skeletal disorders were not affected by the mPGES-1 deficiency. In vivo and ex vivo analyses revealed an impaired proliferation of chondrocytes in cartilage with the mPGES-1 deficiency, at an early stage of fracture healing.
  
  
  CONCLUSIONS
  In these mouse models of skeletal disorders, mPGES-1 was indispensable for bone repair through chondrocyte proliferation, but was not essential for the skeleton under normal physiologic conditions, nor did it play a role in the pathophysiologic conditions of bone loss due to ovariectomy, bone loss due to unloading, or stress-induced OA.
authors.affiliation: University of Tokyo, Tokyo, Japan.
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamakawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Kamekura
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kawamura
authors.forename: Masatomo
authors.initials: M
authors.lastname: Saegusa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamei
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kudo
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Ung-il
authors.initials: UI
authors.lastname: Chung
authors.forename: Kozo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D019902:Chondrocytes / Q000502:physiology; D004195:Disease Models, Animal; D017102:Fracture Healing / Q000502:physiology*; D050723:Fractures, Bone / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics*; D007593:Joint Instability / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D008861:Microsomes / Q000201:enzymology; D010003:Osteoarthritis / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D010052:Ovariectomy; D010641:Phenotype; D000071876:Prostaglandin-E Synthases; D011453:Prostaglandins / Q000378:metabolism; D011859:Radiography; D016474:Weight-Bearing
chemical_list: D011453:Prostaglandins; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse