Arterial Calcification Is Driven by RAGE in Enpp1-/- Mice
Arterial Calcification Is Driven by RAGE in Enpp1-/- Mice
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DOI：
10.1159/000318805
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发表时间：
2011-01-01
影响因子：
1.7
通讯作者：
Terkeltaub, Robert A.
中科院分区：
文献类型：
--
作者：
Cecil, Denise L.;Terkeltaub, Robert A.
背景/目的：异位骨软骨分化由ENPP1催化产生的软骨生成和钙化抑制剂无机焦磷酸(PPI)推动，促进婴儿期全身动脉钙化。晚期糖基化终末产物多配体受体(RAGE)促进动脉粥样硬化和糖尿病心血管和肾脏并发症，也介导软骨细胞分化对RAGE配体钙颗粒蛋白(如S100A11)的反应。在这里，我们测试了与ENPP1缺乏相关的动脉钙化中RAGE的参与。方法：由于Enpp1-/-小鼠异位动脉钙化是依赖P-I的，并受PPI缺乏的影响，采用外源性P-I和碱性磷酸酶对周围PPI的降解，体外研究S100A11和RAGE对小鼠主动脉外植体的影响。结果：S100A11诱导软骨特异性胶原IX/XI的表达和钙化依赖于RAGE，该作用可被内源性RAGE信号抑制剂可溶性RAGE抑制。Enpp1/-主动脉外植体显示P-I刺激的SRAGE释放减少，钙化和IX/XI型胶原表达增加，而外源性SRAGE和Rage基因敲除抑制了这些钙化和IX型胶原的表达。最后，Rage基因敲除抑制了Enpp1-/-小鼠的自发性主动脉原位钙化。结论：培养的Enpp1/-小鼠主动脉外植体可减少P-I刺激的SRAGE释放，RAGE促进Enpp1/-小鼠异位成软骨细胞分化和动脉钙化。版权所有(C)2010 S.Karger AG，巴塞尔
Background/Aims: Ectopic osteochondral differentiation, driven by ENPP1-catalyzed generation of the chondrogenesis and calcification inhibitor inorganic pyrophosphate (PPi), promotes generalized arterial calcification of infancy. The multiligand receptor for advanced glycation end-products (RAGE), which promotes atherosclerosis and diabetic cardiovascular and renal complications, also mediates chondrocyte differentiation in response to RAGE ligand calgranulins such as S100A11. Here, we tested RAGE involvement in ENPP1 deficiency-associated arterial calcification. Methods: Because ectopic artery calcification in Enpp1-/- mice is P-i-dependent and mediated by PPi deficiency, in vitro studies on effects of S100A11 and RAGE on mouse aortic explants were conducted using exogenous P-i, as well as alkaline phosphatase to hydrolyze ambient PPi. Results: S100A11 induced cartilage-specific collagen IX/XI expression and calcification dependent on RAGE in mouse aortic explants that was inhibited by the endogenous RAGE signaling inhibitor soluble RAGE (sRAGE). Enpp1-/- aortic explants demonstrated decreased P-i-stimulated release of sRAGE, and increased calcification and type IX/XI collagen expression that were suppressed by exogenous sRAGE and by Rage knockout. Last, Rage knockout suppressed spontaneous aortic calcification in situ in Enpp1-/- mice. Conclusion: Cultured Enpp1-/- aortic explants have decreased P-i-stimulated release of sRAGE, and RAGE promotes ectopic chondrogenic differentiation and arterial calcification in Enpp1-/- mice. Copyright (C) 2010 S. Karger AG, Basel