Targeted inhibition of tyrosine-protein phosphatase SHP2 as a potential approach for the treatment of fibrosis

在发达国家，纤维性疾病造成了高达45%的死亡，给现代社会带来了重大的社会经济负担。系统性硬化症(SSC)是一种典型的特发性系统性纤维化疾病，具有较高的发病率和死亡率。对于其他纤维性疾病，SSc的特点是肌成纤维细胞聚集，释放过量的细胞外基质。尽管转化生长因子-β(TGFbeta)等成纤维细胞激活的关键因素已被确定，但在纤维化疾病中肌成纤维细胞持续激活的分子机制尚不完全清楚，大多数纤维化疾病尚无有效的靶向治疗方法。我们首次提供证据表明，酪氨酸磷酸酶SHP2可能在SSC等纤维化疾病的发病机制中发挥核心作用。SHP2信号失活可阻止转化生长因子-BATA介导的JAK2/STAT3信号的激活，从而阻止肌成纤维细胞分化和胶原释放。通过基因或药物方法使SHP2失活可抑制依赖于转化生长因子-β的成纤维细胞的激活，并改善实验性纤维化。我们的目标是进一步研究SHP2信号在纤维化疾病中的分子机制，并验证SHP2作为纤维化疾病的治疗靶点。我们计划进一步分析成纤维细胞特异性敲除SHP2在补充性小鼠肝纤维化模型中的抗纤维化作用，确定SHP2在SSC中差异表达的分子机制，表征SHP2对JAK2/STAT3信号的调节，并评价SHP2的药物抑制的抗纤维化作用。我们的发现可能具有翻译意义，因为SHP2的小分子抑制剂目前正被评估用于癌症的临床应用。

Fibrotic diseases contribute to up to 45% of deaths in the developed world and impose a major socioeconomic burden on modern societies. Systemic sclerosis (SSc) is a prototypical idiopathic systemic fibrosing disease with a high morbidity and mortality rate. As for other fibrotic diseases, SSc is characterized by an accumulation of myofibroblasts, which release excessive amounts of extracellular matrix. Although key factors of fibroblast activation such as transforming growth factor-beta (TGFbeta) have been identified, the molecular mechanisms underlying the persistent activation of myofibroblasts in fibrotic disease are incompletely understood and effective targeted therapies are not available for most fibrotic diseases. We provide first evidence that the tyrosine phosphatase SHP2 might play a central role in the pathogenesis of fibrotic diseases such as SSc. Inactivation of SHP2 signaling prevents the TGF-bata mediated activation of JAK2 / STAT3 signaling to prevent myofibroblast differentiation and collagen release. Inactivation of SHP2 by genetic or pharmacologic approaches inhibits TGF-beta-dependent fibroblast activation and ameliorates experimental fibrosis. We aim to further characterize the molecular mechanisms of SHP2 signaling in fibrotic diseases and to validate the SHP2 as a therapeutic target in fibrotic diseases. We plan to further analyze the anti-fibrotic effects of fibroblast-specific knockdown of SHP2 in complementary mouse models of fibrosis, to identify the molecular mechanisms underlying the differential expression of SHP2 in SSc, to characterize the regulation of JAK2 / STAT3 signaling by SHP2 and to evaluate the anti-fibrotic effects of pharmacologic inhibition of SHP2. Our findings may have translational implications as small molecule inhibitors of SHP2 are currently evaluated for clinical use in cancer.