DIFFERENTIATION FACTORS IN CARTILAGE AND BONE FORMATION AND REGENERATION

我们先前已经证明，软骨衍生形态发生蛋白-1的突变可以导致临床上不同的疾病，Grebe(OMIM编号200700)和Hunter-Thompson(OMIM#201250)型软骨发育不良。这两种疾病都有严重的肢体缩短、关节脱位，甚至完全没有某些关节。原位杂交研究表明，CDMP-1是第一个在假定的关节间区特异性表达的基因。这一表达谱可为设计对抗退行性关节疾病的基因治疗方法提供有用的基础。考虑到这一点，我们开始使用瞬时转基因实验来确定软骨和关节特异性调控元件的位置。然而，很明显，CDMP-1启动子/增强子区域上游至少有100kb，这使得试图识别特定元件变得困难。因此，我们最近启动了一种替代方法，利用河豚(河豚)的浓缩基因组。河豚的基因组比哺乳动物的基因组小10倍，但有相似数量的基因，这使得调节区和内含子的大小要小得多。从河豚基因组文库中分离出CDMP-1克隆，并对其外显子/内含子结构进行了研究。-软骨、软骨发育不良、形态发生蛋白

We have previously shown that mutations in Cartilage-Derived Morphogenetic Protein-1 (CDMP-1) can cause the clinically distinct disorders, Grebe (OMIM number 200700) and Hunter- Thompson (OMIM#201250) type chondrodysplasia. Both disorders have severe limb shortening, joint dislocations and even complete absence of certain joints. In situ hybridization studies have shown that CDMP-1 is the first gene to be found specifically expressed in presumptive joint interzones. This expression profile could provide a useful basis for designing gene therapeutic approaches to combat degenerative joint disease. With this in mind we began to determine the location of the cartilage and joint-specific regulatory elements using transient transgenic experiments. It became apparent, however, that the cdmp-1 promoter/enhancer region extends at least 100kb upstream, making it difficult to attempt to identify specific elements. Consequently, we have recently initiated an alternative approach, taking advantage of the condensed genome of the puffer fish (fugu rubripes). The puffer fish genome is 10 times smaller than mammalian genomes, but with a similar number of genes, making the regulatory regions and intron sizes much smaller. Cdmp-1 clones have been isolated from a puffer fish genomic library and the exon/intron structure is being characterized. - cartilage, chondrodysplasia, morphogenetic proteins