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

环氧合酶-2在骨代谢中的作用-cox-2敲除小鼠的分析-

• 批准号: 13671168
• 负责人: OKADA Yosuke
• 金额: $ 1.73万
• 依托单位: University of Occupational and Environmental Health
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671168/
• 关键词: cyclooxygenase-2; bone metabolism; osteoblast

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.

对环加氧酶 2 (COX-2) 基因破坏的小鼠的研究表明，COX-2 产生的前列腺素对于最大程度地刺激破骨细胞分化至关重要。目前的研究探讨了 COX-2 在成骨细胞分化中的作用。与野生型同窝小鼠的培养物 (COX-2^+/+) 相比，两个 COX-2 等位基因 (COX-2^<-/->) 破坏的 5-6 周龄小鼠的骨髓基质细胞 (MSC) 培养物中内源性 PGE_2 的产生显着减少。与COX-2^+/+ 培养物相比，COX-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。将PGE_2添加到COX-2^</-/-> MSC培养物中逆转了COX-2^<+/+>和COX-2^</-/->培养物之间的分化差异。在来自仅一个COX-2基因被破坏的小鼠(COX-2^+/-小鼠)的MSC培养物中，与COX-2^+/+培养物相比，PGE_2产生和ALP染色减少。因此，COX-2^<+/->小鼠可用作研究成年小鼠COX-2缺陷的模型，从而避免COX-2^</-/->小鼠肾脏异常对骨代谢的潜在混杂影响。在体内，与 COX-2^<+/+> 小鼠相比，3 个月大的 COX-2^</-/-> 和 COX-2^<+/-> 小鼠的胫骨骨矿物质含量 (BMC) 降低了 9%，与 COX-2^<+/+> 小鼠相比，COX-2^</-/-> 小鼠的股骨 BMC 降低了 10%。比较COX-2^<+/->小鼠与COX-2^<+/+>小鼠的动态组织形态学分析表明COX-2^<+/->小鼠的骨形成减少。我们得出的结论是，COX-2 表达的缺失会显着损害体外成骨细胞分化，并且可能比体内骨吸收更能减少骨形成。

项目成果

M. Tomita, Y. Okada, et al.: "Effects of a selective EP4 antagonist on osteoclast formation and bone resorption in vitro"Bone. 1. 159-163 (2002)

M. Tomita、Y. Okada 等人：“选择性 EP4 拮抗剂对体外破骨细胞形成和骨吸收的影响”Bone。

Y.Okada: "Cell to cell adhesion through the ICAM-1-/LFA-1 pathway is involved in 1α,25(OH)2D3,PTH and IL-1α-induced osteoclast differentiation and bone resorption"Endocrine J. 49巻. 483-495 (2002)

Y. Okada：“通过 ICAM-1-/LFA-1 途径的细胞间粘附参与 1α,25(OH)2D3、PTH 和 IL-1α 诱导的破骨细胞分化和骨吸收”Endocrine J. 49 卷。 483-495 (2002)

Y.Okada: "Cell to cell adhesion through the ICAM-1/LFA-1 pathway is involved in 1α,25(OH)2D3, PTH and IL-1α-induced osteoclast differentiation and bone resorption"Endocrine J. 49巻. 483-495 (2002)

Y.Okada：“通过 ICAM-1/LFA-1 途径的细胞间粘附参与 1α,25(OH)2D3、PTH 和 IL-1α 诱导的破骨细胞分化和骨吸收”Endocrine J. Vol. 49。 483 -495 (2002)

Y. Okada, Y. Tanaka, et al.: "Role of cyclooxygenase-2 in bone resorption"J UOEH. 21. 185-195 (2003)

Y. Okada、Y. Tanaka 等人：“环氧合酶 2 在骨吸收中的作用”J UOEH。

Y. Tanaka: "The role of chemokines and adhesion molecules in the pathogenesis of rheumatoid arthritis"Drugs of Today. 37. 477-487 (2001)

Y. Tanaka：“趋化因子和粘附分子在类风湿性关节炎发病机制中的作用”《今日药物》。