Combined inhibition of morphogen pathways demonstrates additive antifibrotic effects and improved tolerability
Combined inhibition of morphogen pathways demonstrates additive antifibrotic effects and improved tolerability
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DOI：
10.1136/annrheumdis-2013-204221
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发表时间：
2014-06-01
影响因子：
27.4
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
--
作者：
Distler, Alfiya;Lang, Veronika;Distler, Joerg H. W.
目的Hedgehog、Wnt和Notch是系统性硬化症抗纤维化治疗的靶点。然而，对干细胞再生的干扰可能会使形态生成途径抑制剂的使用复杂化。因此，我们验证了Hedgehog、Wnt和Notch抑制剂联合治疗纤维化可能安全有效的假说。方法通过临床监测、病理评估和对Lgr5阳性的肠道干细胞进行量化来评估不良事件。结果抑制Hedgehog、Wnt和Notch信号通路可剂量依赖地改善博莱霉素诱导的和激活的转化生长因子-β受体I型诱导的纤维化。小剂量Hedgehog/Wnt抑制剂或Hedgehog/Notch抑制剂的联合治疗在预防和治疗方案中都显示出附加的抗纤维化作用。联合治疗耐受性良好。与大剂量单一治疗相比，联合治疗并不减少Lgr5阳性的肠干细胞数量。结论联合抑制形态发生通路具有相加的抗肝纤维化作用。联合疗法耐受性好，与大剂量单一疗法相比，可能不会损害干细胞更新。因此，联合靶向形态形成途径可能有助于克服Hedgehog、Wnt和Notch信号的剂量限制毒性。
Objectives The morphogen pathways Hedgehog, Wnt and Notch are attractive targets for antifibrotic therapies in systemic sclerosis. Interference with stem cell regeneration, however, may complicate the use of morphogen pathway inhibitors. We therefore tested the hypothesis that combination therapies with low doses of Hedgehog, Wnt and Notch inhibitors maybe safe and effective for the treatment of fibrosis.Methods Skin fibrosis was induced by bleomycin and by overexpression of a constitutively active TGF-beta receptor type I. Adverse events were assessed by clinical monitoring, pathological evaluation and quantification of Lgr5-positive intestinal stem cells.Results Inhibition of Hedgehog, Wnt and Notch signalling dose-dependently ameliorated bleomycin-induced and active TGF-beta receptor type I-induced fibrosis. Combination therapies with low doses of Hedgehog/Wnt inhibitors or Hedgehog/Notch inhibitors demonstrated additive antifibrotic effects in preventive as well as in therapeutic regimes. Combination therapies were well tolerated. In contrast with high dose monotherapies, combination therapies did not reduce the number of Lgr5 positive intestinal stem cells.Conclusions Combined inhibition of morphogen pathways exerts additive antifibrotic effects. Combination therapies are well tolerated and, in contrast to high dose monotherapies, may not impair stem cell renewal. Combined targeting of morphogen pathways may thus help to overcome dose-limiting toxicity of Hedgehog, Wnt and Notch signalling.