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

据报道，他汀类化合物可激活BMP-2基因表达，从而产生骨形成。他汀类药物最初被认为是HMG辅酶a还原酶的抑制剂，可显著降低人类和动物血浆胆固醇和甘油三酯水平，并用于治疗高胆固醇血症。在本研究中，研究了染色剂、serivastatin和pravastatin对软骨生长和分化的作用。分别从人和家兔制备了cDNA探针来检测分化标记。利用这些探针，测定了他汀类药物对兔软骨细胞和干细胞原代培养的影响，并获得了以下结果。10^<-5> M时，普伐他汀可使兔软骨细胞中BMP-2 mRNA水平升高24 h。10^<-6> M时，塞伐他汀对兔干细胞中BMP-2 mRNA水平无影响，而印度刺猬mRNA水平明显升高，PTHrP和碱性磷酸酶mRNA水平同时升高。在5 × 10^<-5> m时观察到钙化。在本研究过程中，分离出了新的碱性螺旋-环-螺旋转录因子DEC1和DEC2，并证实它们参与了软骨细胞分化的调控。DEC1和DEC2在各种器官中普遍表达，并具有多种功能，包括调节动物昼夜节律的分子钟新成员。在软骨中也观察到DEC1和DEC2的节律性表达，表明有节律性调节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.