Role of cyclooxygenase-2 in bone metabolism -analysis of cox-2 konckout mice-

对破坏环氧化酶-2（考克斯-2）基因的小鼠的研究表明，由考克斯-2产生的异黄酮类化合物对于破骨细胞分化的最大刺激是关键的。本研究探讨了考克斯-2在成骨细胞分化中的作用。与来自野生型同窝出生小鼠的培养物（考克斯-2 ^</+>）相比，来自两个考克斯-2等位基因均被破坏的5-6周龄小鼠的骨髓基质细胞（MSC）培养物（考克斯-2 ^</->）中内源性PGE_2的产生显著降低。与考克斯-2 ^<+/+>培养物相比，来自考克斯-2 ^<-/->小鼠的MSC培养物具有降低的碱性磷酸酶（ALP）染色和活性、骨钙素mRNA表达和von Kossa染色。向考克斯-2^<-/-> MSC培养物中加入PGE_2逆转了考克斯-2^<+/+>和考克斯-2^<-/->培养物之间的分化差异。与考克斯-2 ^<+/+>培养物相比，在来自仅一个考克斯-2基因被破坏的小鼠（考克斯-2 ^<+/->小鼠）的MSC培养物中，PGE_2产生和ALP染色减少。因此，考克斯-2^<+/->小鼠可用作研究成年小鼠中考克斯-2缺乏的模型，从而避免考克斯-2^<-/->小鼠中肾脏异常对骨代谢的潜在混杂影响。在体内，与考克斯-2^<+/+>小鼠相比，3月龄考克斯-2^<-/->和考克斯-2^<+/->小鼠的胫骨骨矿物质含量（BMC）降低9%，与考克斯-2 ^<+/+>小鼠相比，考克斯-2^<-/->小鼠的股骨BMC降低10%。比较考克斯-2^<+/->小鼠和考克斯-2^<+/+>小鼠的动态组织形态计量学分析表明，考克斯-2^<+/->小鼠的骨形成减少。我们的结论是，考克斯-2表达的情况下，显着损害成骨细胞分化在体外，并可能减少骨形成超过体内吸收。

Studies on mice with disruption of the cyclooxygenase-2 (COX-2) gene have shown that prostaglandins produced by COX-2 are critical for the maximal stimulation of osteoclast differentiation. The current study examined the role of COX-2 in osteoblastic differentiation. Endogenous PGE_2 production was markedly decreased in marrow stromal cell (MSC) cultures from 5-6 wk old mice with disruption of both COX-2 alleles (COX-2^<-/->) compared to cultures from wild type littermates (COX-2^<+/+>). MSC cultures from COX-2^<-/-> mice had decreased alkaline phosphatase (ALP) staining and activity, osteocalcin mRNA expression, and von Kossa staining compared to COX-2^<+/+> cultures. Addition of PGE_2 to COX-2^<-/-> MSC cultures reversed differences in differentiation between COX-2^<+/+> and COX-2^<-/-> cultures. In MSC cultures from mice with only one COX-2 gene disrupted (COX-2^<+/-> mice), PGE_2 production and ALP staining were decreased compared to COX-2^<+/+> cultures. Hence, COX-2^<+/-> mice might be used as models to study COX-2 deficiency in adult mice, thereby avoiding potentially confounding effects of renal abnormalities in COX-2^<-/-> mice on bone metabolism. In vivo, there was a 9% decrease in tibial bone mineral content (BMC) in 3 mo old COX-2^<-/-> and COX-2^<+/-> mice compared to COX-2^<+/+> mice and a 10% decrease in femoral BMC in COX-2^<-/-> mice compared to COX-2^<+/+> mice. Dynamic histomorphometric analyses comparing COX-2^<+/-> mice with COX-2^<+/+> mice suggested decreased bone formation in COX-2^<+/-> mice. We conclude that the absence of COX-2 expression markedly impairs osteoblastic differentiation in vitro and may decrease bone formation more than resorption in vivo.