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.

纤维化是由于成纤维细胞响应有害刺激而连续沉积细胞外基质 （ECM） 引起的;然而，成纤维细胞在此过程中的确切作用尚不清楚。新发现表明蛋白酶ADAMTS12通过重塑 ECM 和激活促纤维化成纤维细胞在驱动纤维化中起关键作用。“根据这些观察结果，我们假设 ADAMTS12 充当控制成纤维细胞激活启动的自分泌开关，包括 [它们] 从血管周围生态位的分离和迁移，”研究人员说。

使用无偏倚的基因表达分析，Konrad Hoeft、Lars Koch 及其同事观察到小鼠和人肾脏损伤后成纤维细胞中 ADAMTS12 的表达上调。Adamts12 缺失的小鼠受到保护，免受肾脏和心脏纤维化的影响，其特征是 ECM 蛋白的上调有限和促纤维化间充质细胞的扩增受限，表明在纤维化过程中具有调节作用。与这些发现一致，永生化 PDGFRβ ⁺ 人间充质肾细胞中 ADAMTS12 的缺失减弱了响应 TGFβ 的 ECM 成分基因 COL1A1 的表达，这与 JAK-STAT 信号传导的下调以及与细胞粘附、细胞迁移和运动相关的途径有关。24 小时的活细胞成像证实，敲除细胞对 TGFβ 表现出迟钝的迁移反应，这是通过活性 ADAMTS12 的表达以及 JAK-STAT 信号的上调来挽救的。从机制上讲，研究人员确定活性ADAMTS12的作用是裂解腓蛋白 HMCN1——一种将细胞拴在膜上的基底膜成分。在 ADAMTS12 过表达细胞中敲低 HMCN1 抑制了它们的迁移，这表明裂解的 HMCN1 肽（在活化的 HMCN1 肽存在下产生ADAMTS12）促进了间充质细胞迁移、活化和纤维化的延续。