ECM remodelling by ADAMTS12 in fibrosis

IF 28.6 1区 医学 Q1 UROLOGY & NEPHROLOGY Nature Reviews Nephrology Pub Date : 2024-10-30 DOI:10.1038/s41581-024-00905-2
Susan J. Allison
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Abstract

Fibrosis results from the continuous deposition of extracellular matrix (ECM) by fibroblasts in response to injurious stimuli; however, the exact roles of fibroblasts in this process are unclear. New findings demonstrate a key role for the protease ADAMTS12 in driving fibrosis through the remodelling of ECM and activation of profibrotic fibroblasts. “On the basis of these observations, we hypothesize that ADAMTS12 serves as an autocrine switch that controls the initiation of fibroblast activation, including [their] detachment and migration from the perivascular niche,” say the researchers.

Using unbiased gene expression analyses, Konrad Hoeft, Lars Koch and colleagues observed upregulated expression of ADAMTS12 in fibroblasts after injury in mouse and human kidneys. Mice with deletion of Adamts12 were protected from kidney and cardiac fibrosis, characterized by the limited upregulation of ECM proteins and restricted expansion of profibrotic mesenchymal cells, indicating a regulatory role in the fibrotic process. In line with these findings, deletion of ADAMTS12 in immortalized PDGFRβ+ human mesenchymal kidney cells attenuated expression of the ECM component gene COL1A1 in response to TGFβ, associated with downregulation of JAK–STAT signalling and of pathways related to cell adhesion, cell migration and locomotion. Live cell imaging over a period of 24 h confirmed that the knockout cells exhibited a blunted migratory response to TGFβ, which was rescued by the expression of active ADAMTS12, along with upregulation of JAK–STAT signalling. Mechanistically, the researchers determined that active ADAMTS12 acts to cleave the fibulin HMCN1 — a component of basement membranes that tethers cells to membranes. Knockdown of HMCN1 in ADAMTS12-overexpressing cells inhibited their migration, which indicates that cleaved HMCN1 peptides (which are produced in the presence of activated ADAMTS12) promote mesenchymal cell migration, activation and perpetuation of fibrosis.

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纤维化过程中 ADAMTS12 对 ECM 的重塑作用
纤维化是成纤维细胞在有害刺激下不断沉积细胞外基质(ECM)的结果;然而,成纤维细胞在这一过程中的确切作用尚不清楚。新的研究结果表明,蛋白酶ADAMTS12在通过重塑ECM和激活坏死性成纤维细胞推动纤维化的过程中起着关键作用。"通过无偏见的基因表达分析,Konrad Hoeft、Lars Koch 及其同事观察到小鼠和人类肾脏损伤后成纤维细胞中 ADAMTS12 的表达上调。缺失Adamts12的小鼠可避免肾脏和心脏纤维化,其特点是ECM蛋白的上调有限,嗜纤维间质细胞的扩增受限,这表明Adamts12在纤维化过程中起着调节作用。与这些发现一致,在永生化的 PDGFRβ+ 人类间充质肾细胞中缺失 ADAMTS12 会降低 ECM 成分基因 COL1A1 对 TGFβ 的表达,这与 JAK-STAT 信号以及与细胞粘附、细胞迁移和运动相关的通路下调有关。24小时的活细胞成像证实,基因敲除细胞对TGFβ的迁移反应减弱,而活性ADAMTS12的表达以及JAK-STAT信号的上调可挽救这种反应。研究人员从机理上确定,活性ADAMTS12的作用是裂解纤维蛋白HMCN1--基底膜的一种成分,可将细胞拴在膜上。在ADAMTS12过表达的细胞中敲除HMCN1抑制了它们的迁移,这表明被裂解的HMCN1肽(在活化的ADAMTS12存在下产生)促进了间充质细胞的迁移、活化和纤维化的延续。
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来源期刊
Nature Reviews Nephrology
Nature Reviews Nephrology 医学-泌尿学与肾脏学
CiteScore
39.00
自引率
1.20%
发文量
127
审稿时长
6-12 weeks
期刊介绍: Nature Reviews Nephrology aims to be the premier source of reviews and commentaries for the scientific communities it serves. It strives to publish authoritative, accessible articles. Articles are enhanced with clearly understandable figures, tables, and other display items. Nature Reviews Nephrology publishes Research Highlights, News & Views, Comments, Reviews, Perspectives, and Consensus Statements. The content is relevant to nephrologists and basic science researchers. The broad scope of the journal ensures that the work reaches the widest possible audience.
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