Klotho deficiency-induced arterial calcification involves osteoblastic transition of VSMCs and activation of BMP signaling,Journal of Cellular Physiology

当前位置： X-MOL 学术 › J. Cell. Physiol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Klotho deficiency-induced arterial calcification involves osteoblastic transition of VSMCs and activation of BMP signaling
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2021-08-08 , DOI: 10.1002/jcp.30541
Yi Lin ₁ , Zhongjie Sun _{1,

2}

Affiliation

Klotho is an aging-suppressor gene. The purpose of this study was to investigate whether Klotho deficiency affects arterial structure. We found that Klotho-deficient (kl/kl) mice developed severe arterial calcification and elastin fragmentation. Klotho-deficient mice demonstrated higher levels of bone morphogenetic proteins (BMP2, BMP4) and runt-related transcription factor 2 (RUNX2) in aortas, indicating that Klotho deficiency upregulates expression of BMP2 and RUNX2 (a key transcription factor in osteoblasts). To exclude the potential involvement of hyperphosphatemia in arterial calcification, Klotho-deficient mice were given a low phosphate diet (0.2%). The low phosphate diet normalized blood phosphate levels and abolished calcification in the lungs and kidneys, but it did not prevent calcification in the aortas in Klotho-deficient mice. Thus, Klotho deficiency per se might play a causal role in the pathogenesis of arterial calcification, which is independent of hyperphosphatemia. In cultured mouse aortic smooth muscle cells (ASMCs), Klotho-deficient serum-induced transition of ASMCs to osteoblasts. Klotho-deficient serum promoted BMP2/vitamin D3-induced protein expression of PIT2 and RUNX2, phosphorylation of SMAD1/5/8 and SMAD2/3, and extracellular matrix calcification. Interestingly, treatments with recombinant Klotho protein abolished BMP2/vitamin D3-induced osteoblastic transition and morphogenesis and calcification. Therefore, Klotho is a critical regulator in the maintenance of normal arterial homeostasis. Klotho deficiency-induced arterial calcification is an active process that involves the osteoblastic transition of SMCs and activation of the BMP2-RUNX2 signaling.

中文翻译：

Klotho 缺乏诱导的动脉钙化涉及 VSMC 的成骨细胞转变和 BMP 信号的激活

Klotho是一种衰老抑制基因。本研究的目的是调查 Klotho 缺乏症是否影响动脉结构。我们发现Klotho缺陷 (kl/kl) 小鼠出现严重的动脉钙化和弹性蛋白碎裂。Klotho缺陷小鼠在主动脉中表现出更高水平的骨形态发生蛋白（BMP2、BMP4）和 runt 相关转录因子 2 (RUNX2)，表明Klotho缺陷会上调 BMP2 和 RUNX2（成骨细胞中的关键转录因子）的表达。为了排除高磷血症对动脉钙化的潜在影响，Klotho-缺陷小鼠被给予低磷酸盐饮食（0.2%）。低磷饮食使血磷水平正常化并消除了肺和肾脏的钙化，但它并没有阻止Klotho的主动脉钙化- 有缺陷的老鼠。因此，Klotho 缺乏本身可能在动脉钙化的发病机制中发挥因果作用，而这与高磷血症无关。在培养的小鼠主动脉平滑肌细胞 (ASMC) 中，Klotho 缺陷血清诱导 ASMC 向成骨细胞转变。Klotho 缺陷血清促进 BMP2/维生素 D3 诱导的 PIT2 和 RUNX2 蛋白表达、SMAD1/5/8 和 SMAD2/3 的磷酸化以及细胞外基质钙化。有趣的是，用重组 Klotho 蛋白进行治疗可消除 BMP2/维生素 D3 诱导的成骨细胞转变、形态发生和钙化。因此，Klotho 是维持正常动脉稳态的关键调节剂。

更新日期：2021-08-08

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11