Mitigating Scar Tissue Formation in Tendon Injuries: Targeting HMGB1, AMPK Activation, and Myofibroblast Migration All at Once.
Mitigating Scar Tissue Formation in Tendon Injuries: Targeting HMGB1, AMPK Activation, and Myofibroblast Migration All at Once.
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DOI：
10.3390/ph16121739
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发表时间：
2023-12-17
期刊：
影响因子：
--
通讯作者：
Wang JH
中科院分区：
文献类型：
--
作者：
Zhang J;Brown R;Hogan MV;Wang JH
肌腱损伤虽然普遍，但对其结构和功能的恢复构成了巨大的挑战。利用同时具有肌腱细胞标志物SCx和肌成纤维细胞标志物α-SMA的转基因小鼠，探讨二甲双胍(Met)对肌腱愈合、修复的影响及其作用机制。我们的研究结果表明，在损伤前或损伤后给予Met，以及两者都能有效地阻止HMGB1释放到肌腱基质中，并降低循环中HMGB1的水平。此外，蛋氨酸处理增加并激活了愈合肌腱内的AMPK和抑制了转化生长因子-β-1的水平。通过阻断α-SMA+肌成纤维细胞的迁移，减少无序的胶原纤维和III型胶原的发生率，肌腱愈合也得到了改善。它还增加了I型胶原的存在。这些结果突出了Met在急性损伤的肌腱中的抗纤维化特性，并提示它有可能被重新用作治疗药物，以减少肌腱损伤时瘢痕组织的形成，这可能在临床上具有深远的意义。
Tendon injuries, while prevalent, present significant challenges regarding their structural and functional restoration. Utilizing alpha-smooth muscle actin (α-SMA)-Ai9-scleraxis (Scx)-green fluorescent protein (GFP) transgenic mice, which exhibit both Scx (a tendon cell marker) and α-SMA (a myofibroblast marker), we explored the effects of metformin (Met) on tendon healing, repair, and its mechanisms of action. Our findings revealed that intraperitoneal (IP) injections of Met, administered before or after injury, as well as both, effectively prevented the release of HMGB1 into the tendon matrix and reduced circulating levels of HMGB1. Additionally, Met treatment increased and activated AMPK and suppressed TGF-β1 levels within the healing tendon. Tendon healing was also improved by blocking the migration of α-SMA+ myofibroblasts, reducing the prevalence of disorganized collagen fibers and collagen type III. It also enhanced the presence of collagen type I. These outcomes highlight Met’s anti-fibrotic properties in acutely injured tendons and suggest its potential for repurposing as a therapeutic agent to minimize scar tissue formation in tendon injuries, which could have profound implications in clinical practice.
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