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

据报道，他汀类化合物可以激活BMP-2基因的表达，从而产生骨形成。他汀类药物最初被认为是HMG CoA还原酶的抑制剂，在人类和动物中，HMG CoA还原酶可显著降低血浆胆固醇和甘油三酯水平，并用于治疗高胆固醇血症。本研究以人和兔为材料，制备了几种不同的cDNAs探针，分别检测了它们对软骨生长和分化的影响，并探讨了它们对软骨分化的影响。普伐他汀可使兔软骨细胞BMP-2mRNA水平在10℃时升高24 h，但对兔干细胞中BMP-2 mRNA水平无明显影响，但可显著提高印度刺猬细胞BMP-2mRNA水平，同时使PTHrP和碱性磷酸酶mRNA水平升高。在本研究过程中，分离到了新的碱性螺旋-环-螺旋转录因子DEC1和DEC2，它们参与了软骨细胞分化的调控。DEC1和DEC2广泛表达于多种器官，具有多种功能，其中包括调节动物昼夜节律的分子时钟新成员。在软骨中也观察到DEC1和DEC2的节律性表达，表明节律性调控软骨细胞生长和分化的重要性。

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.