Neurotrophin-3 acts on the endothelial-mesenchymal transition of heterotopic ossification in rats
Neurotrophin-3 acts on the endothelial-mesenchymal transition of heterotopic ossification in rats
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Neurotropin-3 作用于大鼠异位骨化的内皮-间质转化
DOI：
10.1111/jcmm.14150
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发表时间：
2019-04-01
影响因子：
5.3
通讯作者：
Zhang, Zhongmin
中科院分区：
文献类型：
--
作者：
Zhang, Jie;Wang, Liang;Zhang, Zhongmin
尽管已有大量研究聚焦于异位骨化（HO），但其分子机制仍不明确。内皮 - 间充质转化（EndMT）被认为在异位骨化中起主要作用，且可能部分受神经内分泌细胞因子的调控。神经营养因子 - 3（NT - 3）具有神经内分泌特性，被认为可促进骨骼重塑。在此，我们提出NT - 3可能通过调节EndMT来促进异位骨化的形成。在此，我们利用异位骨化的体内模型和诱导EndMT的体外模型，以阐明NT - 3对异位骨化中EndMT的作用及潜在机制。我们的结果显示，异位骨和软骨源于EndMT，且NT - 3在体内可促进异位骨化的形成。体外实验结果表明，NT - 3上调间充质标志物（FSP - 1、α - SMA和N - 钙黏蛋白）和间充质干细胞（MSC）标志物（STRO - 1、CD44和CD90），并下调内皮标志物（Tie - 1、VE - 钙黏蛋白和CD31）。此外，NT - 3通过激活EndMT增强软骨生成标志物（Sox9）和成骨标志物（OCN和Runx2）。然而，EndMT特异性抑制剂和原肌球蛋白相关激酶C（TrkC）特异性抑制剂在体内和体外均能逆转NT - 3诱导的异位骨化形成和EndMT诱导。总之，我们的研究结果表明，NT - 3在体内和体外均通过调节EndMT促进异位骨化的形成，这为异位骨化的预防和治疗提供了一个新的潜在靶点。
Despite the fact that extensive studies have focused on heterotopic ossification (HO), its molecular mechanism remains unclear. The endothelial-mesenchymal transition (EndMT), which may be partially modulated by neuroendocrine cytokines is thought to play a major role in HO. Neurotrophin-3 (NT-3), which has neuroendocrine characteristics is believed to promote skeletal remodeling. Herein, we suggest that that NT-3 may promote HO formation through regulation of EndMT. Here, we used an in vivo model of HO and an in vitro model of EndMT induction to elucidate the effect and underlying mechanism of NT-3 on EndMT in HO. Our results showed that heterotopic bone and cartilage arose from EndMT and NT-3 promoted HO formation in vivo. Our in vitro results showed that NT-3 up-regulated mesenchymal markers (FSP-1, alpha-SMA and N-cadherin) and mesenchymal stem cell (MSC) markers (STRO-1, CD44 and CD90) and down-regulated endothelial markers (Tie-1, VE-cadherin and CD31). Moreover, NT-3 enhanced a chondrogenesis marker (Sox9) and osteogenesis markers (OCN and Runx2) via activation of EndMT. However, both EndMT specific inhibitor and tropomyosin-related kinase C (TrkC) specific inhibitor rescued NT-3-induced HO formation and EndMT induction in vivo and in vitro. In conclusion, our findings demonstrate that NT-3 promotes HO formation via modulation of EndMT both in vivo and in vitro, which offers a new potential target for the prevention and therapy of HO.