Heparan sulfate abnormalities in exostosis growth plates
Heparan sulfate abnormalities in exostosis growth plates
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DOI：
10.1016/s8756-3282(02)00796-2
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发表时间：
2002-07-01
期刊：
影响因子：
4.1
通讯作者：
Cole, WG
中科院分区：
文献类型：
--
作者：
Hecht, JT;Hall, CR;Cole, WG
遗传性多发性外生骨病（HME）是一种与长骨末端骨外生骨病的发育和生长有关的疾病，是由EXT基因的种系突变引起的。EXT1和EXT2作为糖基转移酶参与硫酸肝素（HS）的生物合成以修饰蛋白聚糖。HS蛋白聚糖由软骨细胞合成，分泌到生长板的细胞外基质中，在生长板信号转导和重塑中发挥关键作用。作为描述外生骨组织形成机制的研究的一部分，我们系统地评估了来自两个HME和两个孤立外生骨组织的四个生长板。突变事件与HS和通常丰富的蛋白聚糖（PLN）的存在/缺失和分布相关。来自HME外生菌的DNA显示出杂合的种系EXT1或EXT2突变，来自一个单独外生菌的DNA显示出体细胞EXT1突变。在这些样本中没有观察到杂合性的损失。4个外生性生长板软骨细胞区HS缺失，PLN减少且分布异常。这些结果表明，尽管在EXT1或EXT2基因中没有发生多种突变事件，但在外生生长板中发现了HS的完全丢失。这种功能性敲除外生性软骨细胞合成HS链的能力，进一步支持了细胞骨架异常和软骨细胞紊乱与异常细胞信号传导相关的观察结果。
Hereditary multiple exostoses (HME), a condition associated with development and growth of bony exostoses at the ends of the long bones, is caused by germline mutations in the EXT genes. EXT1 and EXT2 function as glycosyltransferases that participate in the biosynthesis of heparan sulfate (HS) to modify proteoglycans. HS proteoglycans, synthesized by chondrocytes and secreted to the extracellular matrix of the growth plate, play critical roles in growth plate signaling and remodeling. As part of studies to delineate the mechanism(s) by which an exostosis develops, we have systematically evaluated four growth plates from two HME and two solitary exostoses. Mutational events were correlated with the presence/absence and distribution of HS and the normally abundant proteoglycan, perlecan (PLN). DNA from the HME exostoses demonstrated heterozygous germline EXT1 or EXT2 mutations, and DNA from one solitary exostosis demonstrated a somatic EXT1 mutation. No loss of heterozygosity was observed in any of these samples. The chondrocyte zones of four exostosis growth plates showed absence of HS, as well as diminished and abnormal distribution of PLN. These results indicate that, although multiple mutational events do not occur in the EXT1 or EXT2 genes, a complete loss of HS was found in the exostosis growth plates. This functional knockout of the exostosis chondrocytes' ability to synthesize HS chains further supports the observations of cytoskeletal abnormalities and chondrocyte disorganization associated with abnormal cell signaling.