Physiological role of prostaglandin H2 synthase-2 (COX-2) in bone metabolism

前列腺素H2合成酶（Prostaglandin H2 synthase， COX）产生的前列腺素E2主要作用于骨形成因子和骨吸收因子。cox有两个同工酶，COX-1和COX-2。在本研究中，我们研究了COX-1和COX-2在骨代谢中的生理作用。将IL-1添加到干细胞可分化为破骨细胞的骨髓培养物中，IL-1刺激成骨细胞中COX-2 mRNA和蛋白的表达，COX-2产生的PGE2支持破骨细胞的形成。相反，IL-6、PTH和1,25- (OH) 2维生素D3诱导的破骨细胞形成被认为与前列腺素合成无关，但COX抑制剂也抑制它们诱导的破骨细胞形成。在这项研究中，我们也试图明确前列腺素参与这些系统的机制。为了检验这一点，我们应用了检测系统来测量单个完整细胞的COX活性。加PTH的细胞表达COX活性，不加PTH的细胞不表达COX活性。在抗酒石酸酸性磷酸酶阳性的单核细胞和成骨细胞中观察到PG的合成活性。此外，在培养后期，细胞中PG的活性被COX-2特异性抑制剂NS-398显著抑制。这些数据表明，COX-2在破骨细胞前的表达是破骨细胞向破骨细胞分化所必需的。接下来，我们研究了COX-2在骨形成中的作用。COX-2产生的PGE2刺激成骨细胞生成VFGF，生成的VEGF刺激新合成骨的血管生成，可能具有维持骨的作用。综上所述，本研究清楚地证明COX-2是骨代谢的重要酶。

Prostaglandin E2 produced by prostaglandin H2 synthase (COX) has been to be forcused on the bone forming factor as well as bone resorbing factor. COXs have two isozymes, COX-1 and COX-2. In this study, we investigated that the physiological roles of COX-1 and COX-2 in bone metabolism. When IL-1 added to the bone marrow culture, in which stem cells can be differentiated to osteoclasts, the expression of COX-2 mRNA and protein in osteoblasts were stimulated by IL-1 and the PGE2 produced by COX-2 supported the osteoclast formation.In contrast, the osteoclast formation induced by IL-6, PTH and 1,25- (OH) 2 vitamin D3 was thought to be independent to prostaglandin synthesis, but COX inhibitor also inhibited the osteoclast formation induced by them. In this study, we also tried to be clear the mechanisms for the involvement of prostaglandins in these systems. In order to examine this, we applied the assay system for measuring COX activity in individual intact cell. The cells cultured with PTH expressed COX activity whereas the cells cultured without PTH did not express COX activity. The PG synthetic activity was observed in tartrate-resistant acid phosphatase positive mononucleated cells as well as osteoblastic cells. Moreover, the PG activity in the cells during the late phase of the culture was significantly inhibited by NS-398, a specific inhibitor of COX-2. These data indicate that the COX-2 expression in preosteoclasts is necessary for the differentiation to osteoclasts. Next, we examined the role of COX-2 in bone formation. The PGE2 produced by COX-2 stimulated VFGF production in osteoblasts, and the produced VEGF stimulated angiogenesis in the newly synthesized bone and may have the role of maintenance of bone.In conclusion, it is clearly demonstrated in this study that COX-2 is an important enzyme for bone metabolism.