Zeisberg Michael, Hanai Jun-ichi, Sugimoto Hikaru, Mammoto Tadanori, Charytan David, Strutz Frank, Kalluri Raghu
Center for Matrix Biology, Gastroenterology and Renal Divisions, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Nat Med. 2003 Jul;9(7):964-8. doi: 10.1038/nm888.
Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-beta superfamily. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development. Here we report that BMP-7 reverses TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-beta1-induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-beta1-induced de novo EMT in a mouse model of chronic renal injury. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-beta1 in the regulation of EMT in health and disease.
骨形态发生蛋白（BMP）-7是一种35千道尔顿的同二聚体蛋白，属于转化生长因子（TGF）-β超家族成员。BMP-7在肾脏中的表达最高，其在小鼠体内的基因缺失会导致眼睛、骨骼和肾脏发育严重受损。在此我们报告，BMP-7通过重新诱导E-钙黏蛋白（一种关键的上皮细胞黏附分子）来逆转TGF-β1诱导的上皮-间充质转化（EMT）。此外，我们提供了分子证据，证明在肾小管上皮细胞和乳腺导管上皮细胞中，BMP-7通过Smad依赖途径逆转TGF-β1诱导的EMT。在肾脏中，EMT诱导的肌成纤维细胞积累及随后的肾小管萎缩被认为是慢性肾损伤期间肾纤维化的关键决定因素。因此，我们在慢性肾损伤小鼠模型中测试了BMP-7逆转TGF-β1诱导的新生EMT的潜力。我们的结果表明，全身给予重组人BMP-7可导致严重受损的肾小管上皮细胞修复，并伴有慢性肾损伤的逆转。总体而言，这些结果提供了证据，证明在健康和疾病状态下，BMP-7与TGF-β1在EMT调节中存在相互作用。
