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

对环氧化酶-2 （COX-2）基因破坏的小鼠的研究表明，COX-2产生的前列腺素对最大限度地刺激破骨细胞分化至关重要。目前的研究考察了COX-2在成骨细胞分化中的作用。5-6周龄COX-2等位基因（COX-2^<-/->）均被破坏的小鼠骨髓基质细胞（MSC）的内源性PGE_2产量明显低于野生型同窝小鼠（COX-2^<+/+>）。COX-2^<-/->小鼠的MSC培养与COX-2^<+/+>培养相比，碱性磷酸酶（ALP）染色和活性、骨钙素mRNA表达和von Kossa染色均降低。将PGE_2添加到COX-2^<-/-> MSC培养物中，可以逆转COX-2^<+/+>和COX-2^<-/->培养物之间的分化差异。在只有一个COX-2基因被破坏的小鼠（COX-2^<+/->小鼠）的MSC培养中，与COX-2^<+/+>培养相比，PGE_2的产生和ALP染色减少。因此，COX-2^<+/->小鼠可作为研究成年小鼠COX-2缺乏的模型，从而避免COX-2^<-/->小鼠肾脏异常对骨代谢的潜在混淆影响。在体内，与COX-2^<+/+>小鼠相比，3月龄COX-2^<-/->和COX-2^<+/+>小鼠的胫骨骨矿物质含量（BMC）降低9%，COX-2^<-/->小鼠的股骨BMC与COX-2^<+/+>小鼠相比降低10%。比较COX-2^<+/->小鼠和COX-2^<+/+>小鼠的动态组织形态学分析表明，COX-2^<+/->小鼠骨形成减少。我们的结论是，缺乏COX-2的表达明显地损害了体外成骨细胞的分化，并且可能减少骨形成而不是体内的吸收。

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.