Hyaluronan regulates bone morphogenetic protein-7-dependent prevention and reversal of myofibroblast phenotype.
Hyaluronan regulates bone morphogenetic protein-7-dependent prevention and reversal of myofibroblast phenotype.
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DOI：
10.1074/jbc.m114.625939
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发表时间：
2015-05-01
期刊：
影响因子：
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通讯作者：
Meran S
中科院分区：
文献类型：
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作者：
Midgley AC;Duggal L;Jenkins R;Hascall V;Steadman R;Phillips AO;Meran S
背景：骨形态发生蛋白7（BMP7）可以预防/逆转纤维化，但机制尚不清楚。结果：BMP7 通过细胞表面透明质酸内化到催化内体中来防止/逆转肌成纤维细胞形成。 Hyaluronidase-2 和变体 CD44v7/8 介导此过程。结论：透明质酸的改变对于预防/逆转肌成纤维细胞分化至关重要。意义：描述了 BMP7 作用的新机制，并将 CD44v7/8 和透明质酸酶 2 确定为预防纤维化病理学的潜在靶标。透明质酸 (HA) 促进转化生长因子 (TGF)-β1 驱动的肌成纤维细胞表型。然而，HA 也可以具有疾病限制活性。骨形态发生蛋白 7 (BMP7) 是一种拮抗 TGF-β1 的抗纤维化细胞因子，独立研究表明 HA 可以介导和调节 BMP7 反应。在这项研究中，我们研究了 BMP7 是否可以调节 HA，从而预防/逆转人肺成纤维细胞中 TGF-β1 驱动的肌成纤维细胞分化。结果表明，BMP7 通过一种新机制阻止和逆转 TGF-β1 驱动的肌成纤维细胞分化。 BMP7 促进细胞表面 HA 溶解并内化到细胞质内体中。内体 HA 与 HA 降解酶透明质酸酶 1 和透明质酸酶 2 (Hyal2) 共定位。此外，与 TGF-β1 相比，BMP7 对 CD44 标准和变体同工型表达表现出差异调节。特别是，BMP7 增加了 CD44v7/8 的膜表达。抑制 CD44v7/8 以及阻断细胞表面的 Hyal2 和 Na+/H+ 交换器-1 可阻止 BMP7 驱动的 HA 内化和 BMP7 介导的肌成纤维细胞表型的预防/逆转。总之，显示了 BMP7 拮抗 TGF-β1 的新机制，并确定了 HA 的改变对于介导 BMP7 反应至关重要。此外，我们将 Hyal2 和 CD44v7/8 确定为预防和逆转纤维化病理的新潜在靶点。
Background: Bone morphogenetic protein-7 (BMP7) can prevent/reverse fibrosis, but mechanisms are unclear. Results: BMP7 prevents/reverses myofibroblast formation through cell-surface hyaluronan internalization into catalytic endosomes. Hyaluronidase-2 and variant CD44v7/8 mediate this process. Conclusion: Alterations in hyaluronan are critical in prevention/reversal of myofibroblast differentiation. Significance: A novel mechanism of BMP7 action is described and identifies CD44v7/8 and hyaluronidase-2 as potential targets in preventing fibrotic pathology. Hyaluronan (HA) promotes transforming growth factor (TGF)-β1-driven myofibroblast phenotype. However, HA can also have disease-limiting activity. Bone morphogenetic protein-7 (BMP7) is an antifibrotic cytokine that antagonizes TGF-β1, and isolated studies have demonstrated that HA can both mediate and modulate BMP7 responses. In this study, we investigated whether BMP7 can modulate HA in a manner that leads to prevention/reversal of TGF-β1-driven myofibroblast differentiation in human lung fibroblasts. Results demonstrated that BMP7 prevented and reversed TGF-β1-driven myofibroblast differentiation through a novel mechanism. BMP7 promoted the dissolution and internalization of cell-surface HA into cytoplasmic endosomes. Endosomal HA co-localized with the HA-degrading enzymes, hyaluronidase-1 and hyaluronidase-2 (Hyal2). Moreover, BMP7 showed differential regulation of CD44 standard and variant isoform expression, when compared with TGF-β1. In particular, BMP7 increased membrane expression of CD44v7/8. Inhibiting CD44v7/8 as well as blocking Hyal2 and the Na+/H+ exchanger-1 at the cell-surface prevented BMP7-driven HA internalization and BMP7-mediated prevention/reversal of myofibroblast phenotype. In summary, a novel mechanism of TGF-β1 antagonism by BMP7 is shown and identifies alteration in HA as critical in mediating BMP7 responses. In addition, we identify Hyal2 and CD44v7/8 as new potential targets for manipulation in prevention and reversal of fibrotic pathology.