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Elastin calcification in in vitro models and its prevention by MGP’s N-terminal peptide
Journal of Structural Biology ( IF 3.0 ) Pub Date : 2020-10-12 , DOI: 10.1016/j.jsb.2020.107637
Abhinav Parashar 1 , Ophélie Gourgas 2 , Kirk Lau 3 , Jingjing Li 2 , Lisa Muiznieks 4 , Simon Sharpe 5 , Elaine Davis 6 , Marta Cerruti 3 , Monzur Murshed 7
Affiliation  

Medial calcification has been associated with diabetes, chronic kidney disease, and genetic disorders like pseudoxanthoma elasticum. Recently, we showed that genetic reduction of arterial elastin content reduces the severity of medial calcification in matrix Gla protein (MGP)-deficient and Eln haploinsufficient Mgp−/−;Eln+/− mice. This study suggests that there might be a direct effect of elastin amount on medial calcification. We studied this using novel in vitro systems, which are based on elastin or elastin-like polypeptides. We first examined the mineral deposition properties of a transfected pigmented epithelial cell line that expresses elastin and other elastic lamina proteins. When grown in inorganic phosphate-supplemented medium, these cells deposited calcium phosphate minerals, which could be prevented by an N’-terminal peptide of MGP (m3pS) carrying phosphorylated serine residues. We next confirmed these findings using a cell-free elastin-like polypeptide (ELP3) scaffold, where the peptide prevented mineral maturation. Overall, this work describes a novel cell culture model for elastocalcinosis and examines the inhibition of mineral deposition by the m3pS peptide in this and a cell-free elastin-based scaffold. Our study provides strong evidence suggesting the critical functional roles of MGP’s phosphorylated serine residues in the prevention of elastin calcification and proposes a possible mechanism of their action.



中文翻译:


体外模型中的弹性蛋白钙化及其通过 MGP N 端肽的预防



内侧钙化与糖尿病、慢性肾病和弹力假黄瘤等遗传性疾病有关。最近,我们发现,动脉弹性蛋白含量的遗传减少可降低基质 Gla 蛋白 (MGP) 缺陷和Eln单倍体不足Mgp−/−;Eln+/-小鼠中内侧钙化的严重程度。这项研究表明,弹性蛋白的量可能对内侧钙化有直接影响。我们使用基于弹性蛋白或弹性蛋白样多肽的新型体外系统对此进行了研究。我们首先检查了表达弹性蛋白和其他弹性层蛋白的转染色素上皮细胞系的矿物质沉积特性。当在补充无机磷酸盐的培养基中生长时,这些细胞会沉积磷酸钙矿物质,而携带磷酸化丝氨酸残基的 MGP (m3pS) 的 N' 端肽可以阻止这种情况。接下来,我们使用无细胞弹性蛋白样多肽 (ELP 3 ) 支架证实了这些发现,其中肽阻止矿物质成熟。总体而言,这项工作描述了一种新的弹性钙质沉着症细胞培养模型,并检查了该模型中 m3pS 肽和基于无细胞弹性蛋白的支架对矿物质沉积的抑制作用。我们的研究提供了强有力的证据,表明 MGP 的磷酸化丝氨酸残基在预防弹性蛋白钙化中的关键功能作用,并提出了其可能的作用机制。

更新日期:2020-11-23
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