Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Nat Med. 2012 Feb 5;18(3):396-404. doi: 10.1038/nm.2629.
Molecules associated with the transforming growth factor β (TGF-β) superfamily, such as bone morphogenic proteins (BMPs) and TGF-β, are key regulators of inflammation, apoptosis and cellular transitions. Here we show that the BMP receptor activin-like kinase 3 (Alk3) is elevated early in diseased kidneys after injury. We also found that its deletion in the tubular epithelium leads to enhanced TGF-β1-Smad family member 3 (Smad3) signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3-mediated signaling in the kidney. A structure-function analysis of the BMP-Alk3-BMP receptor, type 2 (BMPR2) ligand-receptor complex, along with synthetic organic chemistry, led us to construct a library of small peptide agonists of BMP signaling that function through the Alk3 receptor. One such peptide agonist, THR-123, suppressed inflammation, apoptosis and the epithelial-to-mesenchymal transition program and reversed established fibrosis in five mouse models of acute and chronic renal injury. THR-123 acts specifically through Alk3 signaling, as mice with a targeted deletion for Alk3 in their tubular epithelium did not respond to therapy with THR-123. Combining THR-123 and the angiotensin-converting enzyme inhibitor captopril had an additive therapeutic benefit in controlling renal fibrosis. Our studies show that BMP signaling agonists constitute a new line of therapeutic agents with potential utility in the clinic to induce regeneration, repair and reverse established fibrosis.
转化生长因子 β（TGF-β）超家族相关分子，如骨形态发生蛋白（BMPs）和 TGF-β，是炎症、细胞凋亡和细胞转化的关键调节因子。在这里，我们发现骨形态发生蛋白受体激活素样激酶 3（Alk3）在损伤后疾病肾脏中早期升高。我们还发现，其在肾小管上皮细胞中的缺失会导致 TGF-β1-Smad 家族成员 3（Smad3）信号的增强、上皮损伤和纤维化，表明 Alk3 介导的信号在肾脏中具有保护作用。BMP-Alk3-BMP 受体，类型 2（BMPR2）配体受体复合物的结构-功能分析，以及合成有机化学，使我们能够构建一个 BMP 信号的小肽激动剂文库，这些激动剂通过 Alk3 受体发挥作用。其中一种肽激动剂 THR-123 抑制炎症、细胞凋亡和上皮-间充质转化程序，并逆转五种急性和慢性肾损伤小鼠模型中的已建立纤维化。THR-123 通过 Alk3 信号特异性起作用，因为其肾小管上皮细胞中 Alk3 靶向缺失的小鼠对 THR-123 治疗没有反应。将 THR-123 与血管紧张素转换酶抑制剂卡托普利联合使用在控制肾纤维化方面具有附加的治疗益处。我们的研究表明，BMP 信号激动剂构成了一类新的治疗药物，具有在临床上诱导再生、修复和逆转已建立纤维化的潜在用途。
