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.
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.
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DOI：
10.1002/art.23158
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发表时间：
2008
影响因子：
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通讯作者：
Kiyofumi Yamakawa;Satoru Kamekura;N. Kawamura;M. Saegusa;D. Kamei;M. Murakami;I. Kudo;S. Uematsu;S. Akira;U. Chung;Kozo Nakamura;H. Kawaguchi
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文献类型：
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作者：
Kiyofumi Yamakawa;Satoru Kamekura;N. Kawamura;M. Saegusa;D. Kamei;M. Murakami;I. Kudo;S. Uematsu;S. Akira;U. Chung;Kozo Nakamura;H. Kawaguchi
目的前列腺素E合成酶（PGES）是前列腺素E(2) （PGE(2)）生物合成的末端酶，是骨和软骨代谢的有效调节剂。在PGES的3种同工酶中，微粒体PGES-1 （mPGES-1）在病理生理事件中对PGE的产生起着最关键的作用(2)。本研究探讨了正常生理和病理生理条件下mPGES-1在mPGES-1缺陷（mPGES-1(-/-)）小鼠骨骼中的作用。方法采用放射学和组织学方法比较mPGES-1（-/-）小鼠及其野生型窝仔的骨骼。建立4种骨骼疾病模型：卵巢切除致骨质丢失模型、后肢卸骨致骨质丢失模型、膝关节不稳定致骨关节炎模型、胫骨中轴截骨致骨折模型。通过免疫组织化学和实时逆转录聚合酶链反应检测PGES酶的表达。在肋软骨软骨细胞离体培养中研究了骨折愈合的细胞机制。结果在正常生理条件下，微粒体PGES-1（-/-）小鼠的骨骼表型未受影响。在骨折模型中，骨折愈合受到mPGES-1缺乏的影响，即使在21天后，一半的小鼠仍处于非骨愈合状态；腺病毒重新导入mPGES-1后，骨折恢复正常愈合。其他骨骼疾病不受mPGES-1缺乏的影响。体内和离体分析显示，在骨折愈合的早期阶段，mPGES-1缺失的软骨中软骨细胞增殖受损。结论在这些骨骼疾病小鼠模型中，mPGES-1是通过软骨细胞增殖修复骨骼所必需的，而不是正常生理条件下骨骼所必需的，也不参与卵巢切除、卸骨、应激性OA等骨质丢失的病理生理条件。
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. CONCLUSION 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.