Study on the effects of statin on growth and differentiation of cartilage

他汀类药物对软骨生长和分化影响的研究

• 批准号: 13671938
• 负责人: NOSHIRO Mitsuhide
• 金额: $ 1.92万
• 依托单位: HIROSHIMA UNIVERSITY
• 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-13671938/
• 关键词: Cholesterol; statin; chondrocyte; stem cell; BMP; circadian rhythm; DEC1; DEC2

Statin compounds are reported to activate BMP-2 gene expression and to generate the bone formation as a result. Statins are originally known to be inhibitors for HMG CoA reductase that strongly lower plasma cholesterol and triglycerides levels in human and animals and are used for the therapy of hypercholesterolemia. In this study, stains, serivastatin and pravastatin are examined for their action on growth and differentiation of cartilage.Several cDNA probes are generated from human and rabbit to examine the differentiation markers. Using these porbes, the effects of statins on primary cultures of chondrocytes and stem cells from rabbits were determined and following results were obtained.Pravastatin increased the Jevel of BMP-2 mRNA in rabbit chondrocytes for 24 h at 10^<-5> M.Serivastatin did not affect the level of BMP-2 mRNA in rabbit stem cells at 10^<-6> M, whereas it markedly increased the level of Indian hedgehog mRNA concomitantly increment of levels of PTHrP and alkaline phosphatase mRNA was observed. Calcification was observed at 5x10^<-5> M.In the course of this study, novel basic helix-loop-helix transcription factors, DEC1 and DEC2, were isolated and proved to be involved in the regulation of chondrocyte differentiation. DEC1 and DEC2 were ubiquitously expressed in various organs and exhibit multiple functions including new members of molecular clock regulation circadian rhythm of animals. The rhythmic expression of DEC1 and DEC2 were also observed in cartilage indicating the importance of rhythmic regulation of chondrocyte growth and differentiation.

据报道，他汀类化合物可激活BMP-2基因表达并因此产生骨形成。他汀类药物最初已知是HMG CoA还原酶的抑制剂，其强烈降低人和动物的血浆胆固醇和甘油三酯水平，并用于治疗高胆固醇血症。本研究以人和兔软骨为材料，制备了几种cDNA探针，检测了它们对软骨生长和分化的影响。结果表明：普伐他汀在10 μ M浓度下作用24 h后，可增加兔软骨细胞BMP-2 mRNA的表达，而西伐<-5>他汀在10 μ M浓度下对兔干细胞BMP-2 mRNA的表达无影响<-6>，但可显著增加兔干细胞Indian hedgehog mRNA的表达，同时可增加PTHrP和碱性磷酸酶mRNA的表达。在5 × 104 μ M时观察到钙化<-5>。在本研究过程中，分离出新型碱性螺旋-环-螺旋转录因子DEC 1和DEC 2，并证明其参与软骨细胞分化的调节。DEC 1和DEC 2广泛表达于多种器官，具有多种功能，包括调节动物昼夜节律的分子钟新成员。DEC 1和DEC 2的节律性表达也在软骨中观察到，表明软骨细胞生长和分化的节律性调节的重要性。

项目成果

Yoshida, E. et al.: "Direct Inhibition of Indian Hedgehog Expression by PTH/PTH-Related Peptide and Up-Regulation by Retinoic Acidin Growth Plate Chondrocyte Cultures"Exp. Cell Res.. 265. 64-72 (2001)

Yoshida, E. 等人：“PTH/PTH 相关肽对 Indian Hedgehog 表达的直接抑制以及视黄酸生长板软骨细胞培养物的上调”实验。

Kim, HG et al.: "Hypocholesteromic effect of bile acid sulfonate analogs in the hamsters"Biol. Pharm. Bull. 24. 218-220 (2001)

Kim, HG 等人：“胆汁酸磺酸盐类似物对仓鼠的低胆固醇作用”Biol。

Ming Shen, Takeshi Kawamoto, Masao Teramoto, Seicho Makihira, Katsumi Fujimoto, Mitsuhide Noshiro, Yukio Kato: "Induction of basic helix-loop-helix protein DEC1 (BHLHB2)/Stra13/Sharp2 in response to the cyclic adenosine monophosphate pathway"Eur.J.Cell Bi

Ming Shen、Takeshi Kawamoto、Masao Teramoto、Seicho Makihira、Katsumi Fujimoto、Mitsuhide Noshiro、Yukio Kato：“诱导碱性螺旋-环-螺旋蛋白 DEC1 (BHLHB2)/Stra13/Sharp2 响应环磷酸腺苷途径”Eur。

Katsumi Fujimoto, Ming Shen, Mitsuhide Noshiro^*, Kazumi Matsubara, Sohei Shingu, Kiyomasa Honda, Eri Yoshida, Ketut Suardita, Yoichi Matsuda, and Yukio Kato: "Molecular Cloning and Characterization of DEC2, a New Member of Basic Helix-Loop-Helix Proteins

Katsumi Fujimoto、Ming Shen、Mitsuhide Noshiro^*、Kazumi Matsubara、Sohei Shingu、Kiyomasa Honda、Eri Yoshida、Ketut Suardita、Yoichi Matsuda 和 Yukio Kato：“基本螺旋环新成员 DEC2 的分子克隆和表征

Fujimoto, K. et al.: "Molecular Cloning and Characterization of DEC2, a New Member of Basic Helix-Loop-Helix Proteins"Biochem. Biophys. Res. Commun.. 260. 164-171 (2001)

Fujimoto, K. 等人：“基本螺旋-环-螺旋蛋白新成员 DEC2 的分子克隆和表征”Biochem。