Serpine1 Knockdown Enhances MMP Activity after Flexor Tendon Injury in Mice: Implications for Adhesions Therapy

Abstract Injuries to flexor tendons can be complicated by fibrotic adhesions, which severely impair the function of the hand. Adhesions have been associated with TGF-β1, which causes upregulation of PAI-1, a master suppressor of protease activity, including matrix metalloproteinases (MMP). In the pr...

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Autores principales:	Margaret A. T. Freeberg, Youssef M. Farhat, Anas Easa, Jacob G. Kallenbach, Dominic W. Malcolm, Mark R. Buckley, Danielle S. W. Benoit, Hani A. Awad
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e5cdfd5cb21341d4a50f60bcc3be2d10
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spelling	oai:doaj.org-article:e5cdfd5cb21341d4a50f60bcc3be2d102021-12-02T15:08:01ZSerpine1 Knockdown Enhances MMP Activity after Flexor Tendon Injury in Mice: Implications for Adhesions Therapy10.1038/s41598-018-24144-12045-2322https://doaj.org/article/e5cdfd5cb21341d4a50f60bcc3be2d102018-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-24144-1https://doaj.org/toc/2045-2322Abstract Injuries to flexor tendons can be complicated by fibrotic adhesions, which severely impair the function of the hand. Adhesions have been associated with TGF-β1, which causes upregulation of PAI-1, a master suppressor of protease activity, including matrix metalloproteinases (MMP). In the present study, the effects of inhibiting PAI-1 in murine zone II flexor tendon injury were evaluated utilizing knockout (KO) mice and local nanoparticle-mediated siRNA delivery. In the PAI-1 KO murine model, reduced adherence of injured tendon to surrounding subcutaneous tissue and accelerated recovery of normal biomechanical properties compared to wild type controls were observed. Furthermore, MMP activity was significantly increased in the injured tendons of the PAI-1 KO mice, which could explain their reduced adhesions and accelerated remodeling. These data demonstrate that PAI-1 mediates fibrotic adhesions in injured flexor tendons by suppressing MMP activity. In vitro siRNA delivery to silence Serpine1 expression after treatment with TGF-β1 increased MMP activity. Nanoparticle-mediated delivery of siRNA targeting Serpine1 in injured flexor tendons significantly reduced target gene expression and subsequently increased MMP activity. Collectively, the data demonstrate that PAI-1 can be a druggable target for treating adhesions and accelerating the remodeling of flexor tendon injuries.Margaret A. T. FreebergYoussef M. FarhatAnas EasaJacob G. KallenbachDominic W. MalcolmMark R. BuckleyDanielle S. W. BenoitHani A. AwadNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Margaret A. T. Freeberg Youssef M. Farhat Anas Easa Jacob G. Kallenbach Dominic W. Malcolm Mark R. Buckley Danielle S. W. Benoit Hani A. Awad Serpine1 Knockdown Enhances MMP Activity after Flexor Tendon Injury in Mice: Implications for Adhesions Therapy
description	Abstract Injuries to flexor tendons can be complicated by fibrotic adhesions, which severely impair the function of the hand. Adhesions have been associated with TGF-β1, which causes upregulation of PAI-1, a master suppressor of protease activity, including matrix metalloproteinases (MMP). In the present study, the effects of inhibiting PAI-1 in murine zone II flexor tendon injury were evaluated utilizing knockout (KO) mice and local nanoparticle-mediated siRNA delivery. In the PAI-1 KO murine model, reduced adherence of injured tendon to surrounding subcutaneous tissue and accelerated recovery of normal biomechanical properties compared to wild type controls were observed. Furthermore, MMP activity was significantly increased in the injured tendons of the PAI-1 KO mice, which could explain their reduced adhesions and accelerated remodeling. These data demonstrate that PAI-1 mediates fibrotic adhesions in injured flexor tendons by suppressing MMP activity. In vitro siRNA delivery to silence Serpine1 expression after treatment with TGF-β1 increased MMP activity. Nanoparticle-mediated delivery of siRNA targeting Serpine1 in injured flexor tendons significantly reduced target gene expression and subsequently increased MMP activity. Collectively, the data demonstrate that PAI-1 can be a druggable target for treating adhesions and accelerating the remodeling of flexor tendon injuries.
format	article
author	Margaret A. T. Freeberg Youssef M. Farhat Anas Easa Jacob G. Kallenbach Dominic W. Malcolm Mark R. Buckley Danielle S. W. Benoit Hani A. Awad
author_facet	Margaret A. T. Freeberg Youssef M. Farhat Anas Easa Jacob G. Kallenbach Dominic W. Malcolm Mark R. Buckley Danielle S. W. Benoit Hani A. Awad
author_sort	Margaret A. T. Freeberg
title	Serpine1 Knockdown Enhances MMP Activity after Flexor Tendon Injury in Mice: Implications for Adhesions Therapy
title_short	Serpine1 Knockdown Enhances MMP Activity after Flexor Tendon Injury in Mice: Implications for Adhesions Therapy
title_full	Serpine1 Knockdown Enhances MMP Activity after Flexor Tendon Injury in Mice: Implications for Adhesions Therapy
title_fullStr	Serpine1 Knockdown Enhances MMP Activity after Flexor Tendon Injury in Mice: Implications for Adhesions Therapy
title_full_unstemmed	Serpine1 Knockdown Enhances MMP Activity after Flexor Tendon Injury in Mice: Implications for Adhesions Therapy
title_sort	serpine1 knockdown enhances mmp activity after flexor tendon injury in mice: implications for adhesions therapy
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/e5cdfd5cb21341d4a50f60bcc3be2d10
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Serpine1 Knockdown Enhances MMP Activity after Flexor Tendon Injury in Mice: Implications for Adhesions Therapy

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