An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis
An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis
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DOI：
10.1038/ng1496
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发表时间：
2005-02-01
期刊：
影响因子：
30.8
通讯作者：
Ikegawa, S
中科院分区：
文献类型：
--
作者：
Kizawa, H;Kou, I;Ikegawa, S
骨关节炎是人类关节炎最常见的形式。我们研究了阿孢菌素（一种在骨关节炎患者的关节软骨中大量表达的细胞外基质成分）在骨关节炎发病机制中的潜在作用。在这里，我们报道了编码阿孢菌素（ASPN）的基因的天冬氨酸（D）重复的多态性与骨关节炎之间的显着关联。在两个独立的膝骨关节炎患者群体中，ASPN 的 D14 等位基因相对于常见的 D13 等位基因的比例过高，并且其频率随着疾病严重程度的增加而增加。 D14 等位基因在髋骨关节炎患者中也较多见。在体外软骨形成模型中，阿孢素可抑制 TGF-β 介导的聚集蛋白聚糖 (AGC1) 和 II 型胶原蛋白 (COL2A1) 基因的表达，并减少蛋白聚糖的积累。对 TGF-β 活性的影响是等位基因特异性的，D14 等位基因比其他等位基因产生更大的抑制作用。体外结合测定显示阿孢菌素和TGF-β之间存在直接相互作用。总而言之，这些发现提供了细胞外基质蛋白、TGF-β活性和疾病之间的另一个功能联系，提出了骨关节炎的新治疗策略。
Osteoarthritis is the most common form of human arthritis. We investigated the potential role of asporin, an extracellular matrix component expressed abundantly in the articular cartilage of individuals with osteoarthritis, in the pathogenesis of osteoarthritis. Here we report a significant association between a polymorphism in the aspartic acid (D) repeat of the gene encoding asporin (ASPN) and osteoarthritis. In two independent populations of individuals with knee osteoarthritis, the D14 allele of ASPN is overrepresented relative to the common D13 allele, and its frequency increases with disease severity. The D14 allele is also overrepresented in individuals with hip osteoarthritis. Asporin suppresses TGF-beta-mediated expression of the genes aggrecan (AGC1) and type II collagen (COL2A1) and reduced proteoglycan accumulation in an in vitro model of chondrogenesis. The effect on TGF-beta activity is allele-specific, with the D14 allele resulting in greater inhibition than other alleles. In vitro binding assays showed a direct interaction between asporin and TGF-beta. Taken together, these findings provide another functional link between extracellular matrix proteins, TGF-beta activity and disease, suggesting new therapeutic strategies for osteoarthritis.