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Ucma/GRP 通过 SMAD 依赖性 BMP 信号抑制磷酸盐诱导的血管平滑肌细胞钙化。

Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling.

机构信息

Department of Biochemistry, School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.

VitaK BV, Maastricht University, Maastricht, The Netherlands.

出版信息

Sci Rep. 2018 Mar 21;8(1):4961. doi: 10.1038/s41598-018-23353-y.

DOI:10.1038/s41598-018-23353-y
PMID:29563538
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5862840/
Abstract

Vascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, β-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.

摘要

血管钙化 (VC) 是指钙磷酸盐晶体在血管壁中的沉积过程，其中血管平滑肌细胞 (VSMCs) 起着核心作用。VC 在慢性肾脏病 (CKD) 患者中非常普遍，部分原因被认为是由磷酸盐失衡引起的。调节 VC 的分子机制尚未完全清楚。在这里，我们提出了一种新的观点，即矿化调节剂 Ucma/GRP（生长板上区和软骨基质相关蛋白/富含 Gla 蛋白）在磷酸盐诱导的 VSMC 钙化中起作用。我们表明，Ucma/GRP 存在于钙化的动脉粥样硬化斑块中，并且在体外钙化的 VSMCs 中高度表达。Ucma/GRP 小鼠的 VSMCs 表现出增加的矿化和骨/软骨生成标志物（BMP-2、Runx2、β-catenin、p-SMAD1/5/8、碱性磷酸酶、骨钙素）的表达，以及矿化抑制剂 MGP 的表达降低，表明 Ucma/GRP 是矿化的抑制剂。使用 BMP 信号抑制剂 noggin 和 SMAD1/5/8 信号抑制剂 dorsomorphin，我们表明 Ucma/GRP 参与抑制 BMP-2-SMAD1/5/8 骨/软骨生成信号通路在高磷酸盐浓度处理的 VSMCs 中。此外，我们首次证明了 Ucma/GRP 与 BMP-2 之间存在直接相互作用。这些结果表明 Ucma/GRP 在调节 VSMCs 的成骨/软骨分化和磷酸盐诱导的矿化中起着重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/5ce9a8f6277e/41598_2018_23353_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/051632cdbcb0/41598_2018_23353_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/1de79eabf060/41598_2018_23353_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/c209ecd70cd0/41598_2018_23353_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/9fd98f3d216d/41598_2018_23353_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/1c35daaf9af4/41598_2018_23353_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/8487ab966ab9/41598_2018_23353_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/5ce9a8f6277e/41598_2018_23353_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/051632cdbcb0/41598_2018_23353_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/1de79eabf060/41598_2018_23353_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/c209ecd70cd0/41598_2018_23353_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/9fd98f3d216d/41598_2018_23353_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/1c35daaf9af4/41598_2018_23353_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/8487ab966ab9/41598_2018_23353_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/869c/5862840/5ce9a8f6277e/41598_2018_23353_Fig7_HTML.jpg

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