Regulation of bona and cartilage metabolism by nucleotide pyrophosphatase (NPPS) -skeletal analysis of ttw mice and its contribution to the human npps gene SNPs -

本研究旨在探讨ttw小鼠矿化诱导的分子机制以及npps基因在临床骨骼疾病中的作用。首先，我们鉴定了软骨特异性基因cystatin 10（Cst 10），该基因在ttw小鼠耳软骨中被高磷饮食诱导。使用小鼠软骨细胞系ATDC 5的体外分析表明，Cst 10可能在软骨细胞分化途径的最后步骤中起重要作用，作为软骨细胞成熟和随后凋亡的诱导剂。Cst 10 ^<-/->小鼠发育正常，没有主要器官的异常，并且在长达52周龄的观察期间，Cst 10 ^<-/->小鼠的bane生长和周转保持与WT相似。我们现在正计划研究是否可以通过与Cst 1杂交来挽救ttw小鼠的异常表型。 ...更多信息 基于核苷酸焦磷酸酶Npps基因负责ttw（OPLL模型小鼠）中的异位骨化的事实，探索人NPPS基因是否与OPLL的易感性和严重性相关的可能性。首先，我们筛选了人类NPPS基因座中的单核苷酸多态性SNP和该基因座中的14个SNP。在180例OPLL患者和265例非OPLL对照之间进行的病例对照关联研究显示，这些SNP之一，IVS 15 - 14 T->C取代在OPLL中更常见，患者p=0.022。OPLL患者骨化椎骨数量的分层研究显示，IVS 15 - 14 T->C替代（p=0.013）以及年轻发病（p=0.046）和女性（p=0.006）与严重骨化相关。虽然病例对照研究和分层研究未能发现SNPs与骨质疏松和骨关节炎的相关性，但我们得出结论，人类NPPS基因中的IVS 15 - 14 T->C取代不仅与OPLL的易感性相关，而且与OPLL的严重程度相关。少

This project investigated the molecular mechanism of mineralization induction in project ttw mice and the contribution of the human npps gene to clinical skeletal disorders.First, we identified a cartilage specific gene cystatin 10 (Cst10 that was induced in the auricular cartilage by a high phosphate diet in ttw mice. In vitro analyses using a mouse chondrogenic cell line, ATDC5, suggested that Cst10 may play an important role in the last steps of the chondrocyte differentiation pathway as an induces of maturation followed by apoptosis of chondrocytes.To further investigate the physiological role of Cst10 in vivo, we created mice lacking the Cst10 one Cst10^<-/-> mice). Cst10^<-/-> mice developed normally without abnormalities of major organs, and bane growth and turnover of Cst10^<-/-> mice remained similar to those of WT during the observation period up to 52 weeks of age. We are now planning examine whether the abnormal phenotype of ttw mice can be rescued by crossing with the Cst1 … More 0^<-/-> mice.Based on the fact that the nucleotide pyrophosphatase Npps gene is responsible for ectopic ossification in ttw, an OPLL model mouse, the possibility was explored whether the human NPPS gene is associated with susceptibility to and severity of OPLL. First we screened for single-nucleotide Polymorphisms SNPs in the human NPPS locus and 14 SNPs in the locus. A case-control association study between 180 OPLL patients and 265 non-OPLL controls showed that one of these SNPs, IVS15-14T->C substitution was more frequently seen in OPLL, Patients p=0.022 than in controls. A stratified study with the number of ossified vertebrae in OPLL patients revealed that IVS15-14T->C substitution (p=0.013), as well as young onset p=0.046 And female sex (p=0.006), were associated with severe ossification. Although the case-control stud ann the stratified study failed to fond association of the SNPs with osteoporosis and osteoarthritis, we conclude that the IVS15-14T->C substitution in the human NPPS gene is associated not only with susceptibility to but also with severity of OPLL. Less