TGF-β1 Suppresses Plasmin and MMP Activity in Flexor Tendon Cells via PAI-1: Implications for Scarless Flexor Tendon Repair.
TGF-β1 Suppresses Plasmin and MMP Activity in Flexor Tendon Cells via PAI-1: Implications for Scarless Flexor Tendon Repair.
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DOI：
10.1002/jcp.24707
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发表时间：
2015-02
影响因子：
5.6
通讯作者：
Awad, Hani A.
中科院分区：
文献类型：
--
作者：
Farhat, Youssef M.;Al-Maliki, Alaa A.;Easa, Anas;O'Keefe, Regis J.;Schwarz, Edward M.;Awad, Hani A.
由手部深度撕裂伤引起的屈肌腱损伤是一个具有挑战性的问题，因为它们通常会导致使人衰弱的粘连，从而阻止患病手指的运动。有证据表明，肌腱粘连以及全身瘢痕形成主要是由多效性生长因子TGF-β1引起的，但对TGF-β1在肌腱愈合中的作用了解甚少。使用肌腱愈合的体外模型，我们先前发现TGF-β1引起肌腱细胞中的基因表达变化，这与瘢痕组织和粘连形成一致，包括抗纤溶蛋白派-1的上调。因此，我们假设TGF-β1通过上调派-1降低负责ECM降解和重塑的蛋白酶（如纤溶酶和MMPs）的活性而促成瘢痕形成和粘连。为了验证我们的假设，我们检测了TGF-β1对肌腱细胞蛋白酶活性的影响。我们发现TGF-β1处理的屈肌腱肌腱细胞活性MMP-2和纤溶酶水平显著降低。有趣的是，TGF-β1对蛋白酶活性的影响在来自不能表达派-1的纯合派-1 KO小鼠的肌腱细胞中被完全消除。我们的研究结果支持了TGF-β1诱导派-1抑制纤溶酶和纤溶酶介导的MMP活性的假设，并提供证据表明派-1可能是预防粘连和促进屈肌腱损伤无瘢痕再生修复的新治疗靶点。
Flexor tendon injuries caused by deep lacerations to the hands are a challenging problem as they often result in debilitating adhesions that prevent the movement of the afflicted fingers. Evidence exists that tendon adhesions as well as scarring throughout the body are largely precipitated by the pleiotropic growth factor, TGF-β1, but the effects of TGF-β1 are poorly understood in tendon healing. Using an in vitro model of tendon healing, we previously found that TGF-β1 causes gene expression changes in tenocytes that are consistent with scar tissue and adhesion formation, including upregulation of the anti-fibrinolytic protein, PAI-1. Therefore, we hypothesized that TGF-β1 contributes to scarring and adhesions by reducing the activity of proteases responsible for ECM degradation and remodeling, such as plasmin and MMPs, via upregulation of PAI-1. To test our hypothesis, we examined the effects of TGF-β1 on the protease activity of tendon cells. We found that flexor tendon tenocytes treated with TGF-β1 had significantly reduced levels of active MMP-2 and plasmin. Interestingly, the effects of TGF-β1 on protease activity were completely abolished in tendon cells from homozygous PAI-1 KO mice, which are unable to express PAI-1. Our findings support the hypothesis that TGF-β1 induces PAI-1, which suppresses plasmin and plasmin-mediated MMP activity, and provide evidence that PAI-1 may be a novel therapeutic target for preventing adhesions and promoting a scarless, regenerative repair of flexor tendon injuries.
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Jorgensen, HG;McLellan, SD;Curtis, ASG
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