Adamts17 is involved in skeletogenesis through modulation of BMP-Smad1/5/8 pathway
Adamts17 is involved in skeletogenesis through modulation of BMP-Smad1/5/8 pathway
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DOI：
10.1007/s00018-019-03188-0
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发表时间：
2019-12-01
影响因子：
8
通讯作者：
Saito, Taku
中科院分区：
文献类型：
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作者：
Oichi, Takeshi;Taniguchi, Yuki;Saito, Taku
微纤原纤维是细胞外基质中普遍存在的元素，在调节转化生长因子β超家族生长因子的生物利用度方面起着至关重要的作用。最近，一些“带有血栓反应蛋白基序的去整合素和金属蛋白酶”(ADAMTS)蛋白被发现可以调节纤维蛋白微原纤维的功能。其中，ADAMTS17基因是Weill-Marchesani综合征(WMS)和Weill-Marchesani样综合征的致病基因，其常见症状是异位晶状体和身材矮小。ADAMTS17也与人类的身高变化有关；然而，ADAMTS17调节骨骼生长的分子机制仍不清楚。在这里，我们产生了Adamts17-/-小鼠来研究Adamts17在骨骼形成中的作用。成年17-/-小鼠概括了WMS，显示出较短的长骨、短指和厚厚的皮肤。17-/-Adamts17-/-小鼠生长板肥大带缩短，纤维蛋白-2沉积增强，提示纤维蛋白-2在微纤维中的掺入增加。用激光显微切割和RNA测序对生长板的基因表达进行综合分析表明，Adamts17基因敲除后骨形态发生蛋白(BMP)信号通路发生了变化。与此一致的是，在生长板的肥大区和成人17/-原代软骨细胞中，磷酸化Smad1水平下调。Adamts17-/-软骨细胞的终末分化延迟，在原代软骨细胞和原始跖骨培养中都观察到，并被BMP治疗阻止。我们的数据表明，Adamts17通过调节BMP-Smad1/5/8途径参与骨形成，可能是通过抑制纤维蛋白-2掺入微纤维。我们的发现将有助于进一步了解疾病机制，并将促进针对WMS的治疗干预措施的发展。
Fibrillin microfibrils are ubiquitous elements of extracellular matrix assemblies that play crucial roles in regulating the bioavailability of growth factors of the transforming growth factor beta superfamily. Recently, several "a disintegrin and metalloproteinase with thrombospondin motifs" (ADAMTS) proteins were shown to regulate fibrillin microfibril function. Among them, ADAMTS17 is the causative gene of Weill-Marchesani syndrome (WMS) and Weill-Marchesani-like syndrome, of which common symptoms are ectopia lentis and short stature. ADAMTS17 has also been linked to height variation in humans; however, the molecular mechanisms whereby ADAMTS17 regulates skeletal growth remain unknown. Here, we generated Adamts17-/- mice to examine the role of Adamts17 in skeletogenesis. Adamts17-/- mice recapitulated WMS, showing shorter long bones, brachydactyly, and thick skin. The hypertrophic zone of the growth plate in Adamts17-/- mice was shortened, with enhanced fibrillin-2 deposition, suggesting increased incorporation of fibrillin-2 into microfibrils. Comprehensive gene expression analysis of growth plates using laser microdissection and RNA sequencing indicated alteration of the bone morphogenetic protein (BMP) signaling pathway after Adamts17 knockout. Consistent with this, phospho-Smad1 levels were downregulated in the hypertrophic zone of the growth plate and in Adamts17-/- primary chondrocytes. Delayed terminal differentiation of Adamts17-/- chondrocytes, observed both in primary chondrocyte and primordial metatarsal cultures, and was prevented by BMP treatment. Our data indicated that Adamts17 is involved in skeletal formation by modulating BMP-Smad1/5/8 pathway, possibly through inhibiting the incorporation of fibrillin-2 into microfibrils. Our findings will contribute to further understanding of disease mechanisms and will facilitate the development of therapeutic interventions for WMS.