Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
IUBMB Life. 2019 May;71(5):653-662. doi: 10.1002/iub.2013. Epub 2019 Jan 28.
Peritendinous fibrosis, which leads to impaired tendon function, is a clinical problem worldwide, and it is urgent to explore potential ways to reduce the formation of peritendinous adhesion. Several studies have demonstrated the biological roles of hydroxycamptothecin (HCPT) in inhibiting fibrosis in different tissues. In this study, we investigated whether HCPT could inhibit tendon fibrosis in vitro. Our results revealed that HCPT inhibited transforming growth factor (TGF)-β1-induced cell viability of human fibroblasts, decreased excessive cell hyperproliferation and promoted fibroblasts apoptosis. In addition, HCPT treatment also inhibited expression of fibrosis genes COL3A1 and α-smooth muscle actin (α-SMA). In terms of mechanism, we pretreated fibroblasts with the endoplasmic reticulum stress (ER) inhibitor salubrinal and RNA-dependent protein kinase-like ER kinase (PERK) short hairpin RNA, these treatments abolished the inhibitory effects of HCPT on fibrosis, thereby suggesting that HCPT's inhibition of TGF-β1-induced tendon fibrosis might be mediated by the PERK signaling pathway in vitro. In conclusion, our results suggested that HCPT had protective effects on peritendinous tissue fibrosis and might be promising in future clinical applications. © 2019 IUBMB Life, 71(5):653-662, 2019.
腱周纤维化会导致肌腱功能受损，是一个全球性的临床问题，因此迫切需要探索减少腱周粘连形成的潜在方法。有几项研究表明羟基喜树碱（HCPT）在抑制不同组织纤维化方面具有生物学作用。在本研究中，我们研究了 HCPT 是否可以抑制体外肌腱纤维化。我们的结果表明，HCPT 抑制转化生长因子（TGF）-β1 诱导的人成纤维细胞活力，减少细胞过度增殖并促进成纤维细胞凋亡。此外，HCPT 处理还抑制纤维化基因 COL3A1 和 α-平滑肌肌动蛋白（α-SMA）的表达。就机制而言，我们用内质网应激（ER）抑制剂 salubrinal 和 PERK 短发夹 RNA 预处理成纤维细胞，这些处理消除了 HCPT 对纤维化的抑制作用，表明 HCPT 抑制 TGF-β1 诱导的肌腱纤维化可能是通过体外 PERK 信号通路介导的。总之，我们的研究结果表明 HCPT 对腱周组织纤维化具有保护作用，在未来的临床应用中可能具有广阔的前景。
