Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency
Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency
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DOI：
10.1096/fj.201800753rr
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发表时间：
2019-02-01
期刊：
影响因子：
4.8
通讯作者：
Le Goff, Carine
中科院分区：
文献类型：
--
作者：
Delhon, Laure;Mahaut, Clementine;Le Goff, Carine
去整合素和带有血栓反应蛋白模体2(ADAMTSL2)基因的金属蛋白酶的突变是常染色体隐性遗传性遗传性先天性发育不良的原因，其特征是身材矮小、四肢短小和骨骼异常。然而，ADAMTSL2的确切功能尚不清楚。为了阐明这种蛋白在骨骼发育中的作用，我们建立了补充性基因敲除(KO)小鼠模型，该小鼠的全部或软骨细胞Adamtsl2缺乏。我们观察到Adamtsl2KO小鼠的骨骼异常使人联想到人类的表型。Adamtsl2缺失影响生长板的形成，软骨细胞分化和增殖异常。此外，在缺乏Adamtsl2的肢体中也显示出转化生长因子信号的损伤。进一步研究发现，Adamtsl2KO软骨细胞未能形成由纤维蛋白1和潜在的转化生长因子结合蛋白1纤维组成的微纤维网络。软骨细胞Adamtsl2KO小鼠也表现出侏儒症。这些研究揭示了Adamtsl2通过调节微纤维网络维持生长板ECM的功能。Delhon，L.，Mahaut，C.，Goudin，N.，Gaudas，E.，Piquand，K.，Le Goff，W.，Cormier-Daire，V.，Le Goff，C.在Adamtsl2缺乏症中软骨形成和微纤维网络的损害。
Mutations in the a disintegrin and metalloproteinase with thrombospondin motif-like 2 (ADAMTSL2) gene are responsible for the autosomal recessive form of geleophysic dysplasia, which is characterized by short stature, short extremities, and skeletal abnormalities. However, the exact function of ADAMTSL2 is unknown. To elucidate the role of this protein in skeletal development, we generated complementary knockout (KO) mouse models with either total or chondrocyte Adamtsl2 deficiency. We observed that the Adamtsl2 KO mice displayed skeletal abnormalities reminiscent of the human phenotype. Adamtsl2 deletion affected the growth plate formation with abnormal differentiation and proliferation of chondrocytes. In addition, a TGF- signaling impairment in limbs lacking Adamtsl2 was demonstrated. Further investigations revealed that Adamtsl2 KO chondrocytes failed to establish a microfibrillar network composed by fibrillin1 and latent TGF- binding protein 1 fibrils. Chondrocyte Adamtsl2 KO mice also exhibited dwarfism. These studies uncover the function of Adamtsl2 in the maintenance of the growth plate ECM by modulating the microfibrillar network.Delhon, L., Mahaut, C., Goudin, N., Gaudas, E., Piquand, K., Le Goff, W., Cormier-Daire, V., Le Goff, C. Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency.