Regulation of skeletal cell differentiation by BMP and its inhibitor, noggin

BMP 及其抑制剂 noggin 对骨骼细胞分化的调节

• 批准号: 11671836
• 负责人: NIFUJI Akira
• 金额: $ 2.24万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671836/
• 关键词: BMP; Cartilage; noggin; noggin

Coordinated interaction between signaling molecules are prerequisite for normal skeletal development. Recently, noggin was shown to interact with BMPs to inhibit their binding to receptor and has been also reported to function in cartilage morphogenesis in mammals. However, presice roles of noggin in cartilage formation and interaction beweeen noggin and BMPs during skeletogenesis were not yet to be elucidated. In this study, we examined possible roles of noggin in cartilage formation and investigated functional relationship between noggin and BMPs during skeletogenesis. Mainly two approaches were undertaken for these purposes. One is to analyze expression patterns of noggin during mouse embryogenesis and compare those or BMPs by in situ hybridization. The other is that mouse long bone organ culture was performed in vitro and noggin or BMPs protein were added to the medium or impalnted with a carrier into limb primordia to examine the effects of those proteins on long bone development. … More Noggin mRNA started to be expressed at the onset of skeletal condensation on day 11.5 dpc in cranial, appendicular and axial skeleton. The expression of noggin transcrpts persisted in cartilage until prehypertrophic stage on 15.5dpc. Exression domain of BMP7 and BMP4 transcipts are compasatory for that of noggin durig limb bone development from day 11.5dpc to 15.5dpc. Implantation of BMP7 protein inthe limb primordia of 11.5 dpc embryos induced noggin expression and this effects were not observed on 14.5 dpc limb. When isolated femur or fibula of 14.5 dpc were cultured in the presence of noggin recombinant protein. cartilage development were hampered in comparison with control. Addition of BMP7 protein in limb long bone culture resulted in overgrowth of cartilage and this effect was cancelled when noggin and BMP7 proteins were added simultaneously . These results indicate that noggin, expressed during chondrogenesis, negatively regulated cartilage development and noggin expression is induced by BMP7 in the early skeletogenesis, and suggest that noggin function as a negative signal in the negative feed back loop of BMP signaling in skeletal development. Less

信号分子之间的协调相互作用是骨骼正常发育的先决条件。最近，noggin被证明与bmp相互作用，抑制它们与受体的结合，也有报道称在哺乳动物软骨形态发生中起作用。然而，noggin在软骨形成中的重要作用以及在骨骼形成过程中noggin和bmp之间的相互作用尚未被阐明。在这项研究中，我们研究了noggin在软骨形成中的可能作用，并研究了骨骼形成过程中noggin和bmp之间的功能关系。为此目的主要采取了两种方法。一是分析小鼠胚胎发生过程中noggin的表达模式，并通过原位杂交对其与bmp进行比较。另一种方法是体外培养小鼠长骨器官，将noggin或bmp蛋白添加到培养基中或与载体一起植入肢体原基，观察这些蛋白对长骨发育的影响。在颅骨、尾骨和轴骨中，在第11.5天骨骼凝结开始时，Noggin mRNA开始大量表达。在15.5dpc的软骨中，noggin转录本的表达一直持续到增生前阶段。BMP7和BMP4的表达域与noggin在肢骨发育11.5 ~ 15.5天的表达域一致。BMP7蛋白植入11.5 dpc胚胎肢体原基诱导noggin表达，14.5 dpc胚胎未观察到这种影响。用noggin重组蛋白培养14.5 dpc的股骨或腓骨。与对照组相比，软骨发育受到阻碍。肢体长骨培养中添加BMP7蛋白可导致软骨过度生长，同时添加noggin和BMP7蛋白可消除这种影响。这些结果表明，在软骨形成过程中表达的noggin负向调节软骨发育，而在骨骼形成早期，BMP7诱导了noggin的表达，并提示noggin在骨骼发育过程中作为BMP信号负反馈回路中的负信号。少

项目成果

Nifuji, A. et al: "Noggin expression in a mesodermal pluripotent cell line C1 and its regulation by BMP."J. Cell. Biochem. 72. 437-444 (1999)

Nifuji, A. 等人：“中胚层多能细胞系 C1 中的 Noggin 表达及其 BMP 的调节。”

Nifuji,A et al.: "Coordinated expression of noggin and BMPs during early skeletogenesis and induction of noggin expression by BMP7"Journal of Bone and Mineral Research. 14. 2057-2066 (1999)

Nifuji,A 等人：“早期骨骼发生过程中头蛋白和 BMP 的协调表达以及 BMP7 诱导头蛋白表达”《骨与矿物研究杂志》。

Nifuji, A.and Noda, M.: "Coordinated expression of noggin and BMPs during early skeletogenesis and induction of noggin expression by BMP7."Journal of Bone and Mineral Research. 14. 2057-2066 (1999)

Nifuji, A. 和 Noda, M.：“早期骨骼发生期间头蛋白和 BMP 的协调表达以及 BMP7 诱导头蛋白表达。”骨与矿物质研究杂志。

Takazawa, Y., Nifuji, A., Mataga, N., Yamauchi, Y., Kurosawa, H., and Noda, M.: "Articular cartilage cells immortalized by a temperature sensitive mutant of SV40 large T antigen survive and form cartilage tissue in articular cartilage environment."Journal

Takazawa, Y.、Nifuji, A.、Mataga, N.、Yamauchi, Y.、Kurosawa, H. 和 Noda, M.：“由 SV40 大 T 抗原的温度敏感突变体永生化的关节软骨细胞存活并形成软骨

Takazawa,Y: "An osieogenesis-reiaied transcription factor,core-binding lactor A1, is constitulively expressed in the chondrocylic cell TC6, and its expression is upregulated by bone morphogenetic protein-2. "Journal of Endocrinology. 165. 579-586 (2000)

Takazawa,Y：“一种成骨相关转录因子，核心结合乳糖 A1，在软骨细胞 TC6 中持续表达，并且其表达受到骨形态发生蛋白 2 的上调。”《内分泌学杂志》。