Contribution of new prostaglandin E_2 synthase to bone resorptive pathology and clinical application of PGES inhibitor

在前列腺素E合成酶（PGES）的三种同工酶中，只有微粒体PGES-1（mPGES-1）是与环氧合酶（考克斯）-2功能性偶联的诱导酶。首先，我们证实了在培养的小鼠原代成骨细胞和骨髓细胞中，只有mPGES-1被骨吸收细胞因子诱导。阻断mPGES-1表达的反义寡核苷酸不仅抑制PGE_2的产生，而且抑制细胞因子刺激的破骨细胞生成和骨吸收。接下来，我们分析了mPGES-1敲除（KO）小鼠的表型。mPGES-1 KO小鼠在生理条件下正常发育和生长，包括骨骼在内的主要器官无异常。因此，我们使用小鼠实验模型研究了mPGES-1在几种病理条件下的参与。相对于WT小鼠，KO小鼠中通过醋酸扭体反应评估的疼痛伤害感受和通过皮下植入棉线诱导的背部炎性肉芽组织形成显著减少。在胶原抗体诱导的关节炎模型中，mPGES-1 KO小鼠不仅表现出对炎症的抑制，而且还表现出对关节破坏的抑制。在KO和WT小鼠中观察到卵巢切除术和尾部悬吊卸载后的骨减少相似。与WT小鼠相比，mPGES-1 KO小鼠的骨折愈合受到抑制，骨痂形成较小。使用腺病毒载体将mPGES-1重新引入KO断裂部位恢复了愈伤组织形成。在实验性膝关节OA模型中，在WT和mPGES-1 KO小鼠中观察到类似的软骨破坏。mPGES-1抑制剂有望成为一种高选择性的药物，可替代考克斯-2抑制剂，但在骨折患者中应谨慎使用。

Among three isozymes of prostaglandin E synthase (PGES), only microsomal PGES-1 (mPGES-1) is the inducible enzyme functionally coupled with cyclooxygenase (COX)-2. First, we confirmed that only mPGES-1 was induced by bone resorptive cytokines in cultured mouse primary osteoblasts and bone marrow cells. An antisense oligonucleotide blocking mPGES-1 expression inhibited not only PGE_2 production, but also osteoclastogenesis and bone resorption stimulated by the cytokines. Next, we analyzed the phenotypes of mPGES-1 knockout (KO) mice. mPGES-1 KO mice developed and grew normally without abnormalities of major organs including bone under physiological conditions. Hence, we investigated the involvement of mPGES-1 in several pathological conditions using mouse experimental models. Pain nociception assessed by the acetic acid writhing response, and inflammatory granulation tissue formation in the dorsum induced by subcutaneous implantation of a cotton thread were significantly reduced in KO mice relative to WT mice. In collagen antibody-induced arthritis model, mPGES-1 KO mice exhibited inhibition not only of inflammation, but also of joint destruction. Bone decreases after ovariectomy and unloading by tail-suspension were similarly seen in KO and WT mice. Fracture healing was inhibited in mPGES-1 KO mice with smaller callus formation as compared with WT mice. Reintroduction of mPGES-1 to the KO fractured site using an adenovirus vector restored the callus formation. In an experimental knee OA model, cartilage destruction was similarly seen in WT and mPGES-1 KO mice. An inhibitor of mPGES-1 is expected to be a highly selective agent against several disorders, and might replace COX-2 inhibitors ; however, it should be cautiously applied to patients with bone fracture.