{"title":"高钙环境通过TFPI-2-DCHS1-ALP/ENPP1轴诱导肾间质成纤维细胞异位钙化，从而参与兰德尔斑块的形成。","authors":"Minghui Liu, Zhi Liu, Fang Huang, Hequn Chen, Zhongqing Yang, Zewu Zhu","doi":"10.1007/s00240-024-01622-y","DOIUrl":null,"url":null,"abstract":"<p><p>Randall's plaques (RP) serve as anchoring sites for calcium oxalate (CaOx) stones, but the underlying mechanism remains unclear. Renal interstitium with a high-calcium environment is identified as pathogenesis of RP formation where the role of human renal interstitial fibroblasts (hRIFs) was highlighted. Our study aims to elucidate the potential mechanism by which a high-calcium environment drives ectopic calcification of hRIFs to participate in RP formation. Alizarin Red staining demonstrated calcium nodules in hRIFs treated with high-calcium medium. Utilizing transcriptome sequencing, tissue factor pathway inhibitor-2 (TFPI-2) was found to be upregulated in high-calcium-induced hRIFs and RP tissues, and TFPI-2 promoted high-calcium-induced calcification of hRIFs. Subsequently, the downstream regulator of TFPI2 was screened by transcriptome sequencing analysis of hRIFs with TFPI-2 knockdown or overexpressed. Dachsous Cadherin Related 1 (DCHS1) knockdown was identified to suppress the calcification of hRIFs enhanced by TFPI-2. Further investigation revealed that TFPI-2/DCHS1 axis promoted high-calcium-induced calcification of hRIFs via disturbing the balance of ENPP1/ALP activities, but without effect on the canonical osteogenic markers, such as osteopontin (OPN), osteogenic factors runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2). In summary, our study mimicked the high-calcium environment observed in CaOx stone patients with hypercalciuria, and discovered that the high-calcium drove ectopic calcification of hRIFs via a novel TFPI-2-DCHS1-ALP/ENPP1 pathway rather than adaption of osteogenic phenotypes to participate in RP formation.</p>","PeriodicalId":23411,"journal":{"name":"Urolithiasis","volume":"52 1","pages":"122"},"PeriodicalIF":2.0000,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A high-calcium environment induced ectopic calcification of renal interstitial fibroblasts via TFPI-2-DCHS1-ALP/ENPP1 axis to participate in Randall's plaque formation.\",\"authors\":\"Minghui Liu, Zhi Liu, Fang Huang, Hequn Chen, Zhongqing Yang, Zewu Zhu\",\"doi\":\"10.1007/s00240-024-01622-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Randall's plaques (RP) serve as anchoring sites for calcium oxalate (CaOx) stones, but the underlying mechanism remains unclear. Renal interstitium with a high-calcium environment is identified as pathogenesis of RP formation where the role of human renal interstitial fibroblasts (hRIFs) was highlighted. Our study aims to elucidate the potential mechanism by which a high-calcium environment drives ectopic calcification of hRIFs to participate in RP formation. Alizarin Red staining demonstrated calcium nodules in hRIFs treated with high-calcium medium. Utilizing transcriptome sequencing, tissue factor pathway inhibitor-2 (TFPI-2) was found to be upregulated in high-calcium-induced hRIFs and RP tissues, and TFPI-2 promoted high-calcium-induced calcification of hRIFs. Subsequently, the downstream regulator of TFPI2 was screened by transcriptome sequencing analysis of hRIFs with TFPI-2 knockdown or overexpressed. Dachsous Cadherin Related 1 (DCHS1) knockdown was identified to suppress the calcification of hRIFs enhanced by TFPI-2. Further investigation revealed that TFPI-2/DCHS1 axis promoted high-calcium-induced calcification of hRIFs via disturbing the balance of ENPP1/ALP activities, but without effect on the canonical osteogenic markers, such as osteopontin (OPN), osteogenic factors runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2). In summary, our study mimicked the high-calcium environment observed in CaOx stone patients with hypercalciuria, and discovered that the high-calcium drove ectopic calcification of hRIFs via a novel TFPI-2-DCHS1-ALP/ENPP1 pathway rather than adaption of osteogenic phenotypes to participate in RP formation.</p>\",\"PeriodicalId\":23411,\"journal\":{\"name\":\"Urolithiasis\",\"volume\":\"52 1\",\"pages\":\"122\"},\"PeriodicalIF\":2.0000,\"publicationDate\":\"2024-08-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Urolithiasis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00240-024-01622-y\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"UROLOGY & NEPHROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Urolithiasis","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00240-024-01622-y","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
引用次数: 0
摘要
兰德尔斑块（RP）是草酸钙（CaOx）结石的锚定点，但其基本机制仍不清楚。高钙环境下的肾间质被认为是 RP 形成的发病机制，其中人肾间质成纤维细胞（hRIFs）的作用尤为突出。我们的研究旨在阐明高钙环境驱动 hRIFs 异位钙化参与 RP 形成的潜在机制。茜素红染色显示了经高钙培养基处理的 hRIFs 中的钙结节。通过转录组测序，发现组织因子通路抑制因子-2（TFPI-2）在高钙诱导的 hRIFs 和 RP 组织中上调，并且 TFPI-2 促进了高钙诱导的 hRIFs 的钙化。随后，通过对敲除或过表达 TFPI-2 的 hRIFs 进行转录组测序分析，筛选出了 TFPI2 的下游调节因子。结果发现，敲除Dachsous Cadherin Related 1（DCHS1）可抑制TFPI-2增强的hRIFs钙化。进一步研究发现，TFPI-2/DCHS1轴通过扰乱ENPP1/ALP活性的平衡促进了高钙诱导的hRIFs钙化，但对典型的成骨标志物，如骨生成素（OPN）、成骨因子runt相关转录因子2（RUNX2）、骨形态发生蛋白2（BMP2）没有影响。总之，我们的研究模拟了在高钙尿症钙结石患者体内观察到的高钙环境，发现高钙通过一种新的TFPI-2-DCHS1-ALP/ENPP1途径驱动hRIFs异位钙化，而不是成骨表型的适应性参与RP的形成。
A high-calcium environment induced ectopic calcification of renal interstitial fibroblasts via TFPI-2-DCHS1-ALP/ENPP1 axis to participate in Randall's plaque formation.
Randall's plaques (RP) serve as anchoring sites for calcium oxalate (CaOx) stones, but the underlying mechanism remains unclear. Renal interstitium with a high-calcium environment is identified as pathogenesis of RP formation where the role of human renal interstitial fibroblasts (hRIFs) was highlighted. Our study aims to elucidate the potential mechanism by which a high-calcium environment drives ectopic calcification of hRIFs to participate in RP formation. Alizarin Red staining demonstrated calcium nodules in hRIFs treated with high-calcium medium. Utilizing transcriptome sequencing, tissue factor pathway inhibitor-2 (TFPI-2) was found to be upregulated in high-calcium-induced hRIFs and RP tissues, and TFPI-2 promoted high-calcium-induced calcification of hRIFs. Subsequently, the downstream regulator of TFPI2 was screened by transcriptome sequencing analysis of hRIFs with TFPI-2 knockdown or overexpressed. Dachsous Cadherin Related 1 (DCHS1) knockdown was identified to suppress the calcification of hRIFs enhanced by TFPI-2. Further investigation revealed that TFPI-2/DCHS1 axis promoted high-calcium-induced calcification of hRIFs via disturbing the balance of ENPP1/ALP activities, but without effect on the canonical osteogenic markers, such as osteopontin (OPN), osteogenic factors runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2). In summary, our study mimicked the high-calcium environment observed in CaOx stone patients with hypercalciuria, and discovered that the high-calcium drove ectopic calcification of hRIFs via a novel TFPI-2-DCHS1-ALP/ENPP1 pathway rather than adaption of osteogenic phenotypes to participate in RP formation.
期刊介绍：
Official Journal of the International Urolithiasis Society
The journal aims to publish original articles in the fields of clinical and experimental investigation only within the sphere of urolithiasis and its related areas of research. The journal covers all aspects of urolithiasis research including the diagnosis, epidemiology, pathogenesis, genetics, clinical biochemistry, open and non-invasive surgical intervention, nephrological investigation, chemistry and prophylaxis of the disorder. The Editor welcomes contributions on topics of interest to urologists, nephrologists, radiologists, clinical biochemists, epidemiologists, nutritionists, basic scientists and nurses working in that field.
Contributions may be submitted as full-length articles or as rapid communications in the form of Letters to the Editor. Articles should be original and should contain important new findings from carefully conducted studies designed to produce statistically significant data. Please note that we no longer publish articles classified as Case Reports. Editorials and review articles may be published by invitation from the Editorial Board. All submissions are peer-reviewed. Through an electronic system for the submission and review of manuscripts, the Editor and Associate Editors aim to make publication accessible as quickly as possible to a large number of readers throughout the world.
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