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

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Serpine1 Knockdown Enhances MMP Activity After Flexor Tendon Injury in Mice: Implications for Adhesions Therapy www.nature.com/scientificreports OPEN Serpine1 Knockdown Enhances MMP Activity after Flexor Tendon Injury in Mice: Implications for Received: 20 December 2017 Accepted: 27 March 2018 Adhesions Therapy Published: xx xx xxxx Margaret A. T. Freeberg1,2, Youssef M. Farhat1,2, Anas Easa2, Jacob G. Kallenbach1,2, Dominic W. Malcolm1,2, Mark R. Buckley1,2, Danielle S. W. Benoit1,2,3 & Hani A. Awad1,2,3 Injuries to fexor tendons can be complicated by fbrotic 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 efects of inhibiting PAI-1 in murine zone II fexor 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 signifcantly 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 fbrotic adhesions in injured fexor 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 fexor tendons signifcantly 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 fexor tendon injuries. Flexor tendon injuries in zone II of the hand are prone to the formation of debilitating adhesions, resulting from fbrotic scar tissue, which obstructs tendon gliding and severely impairs fexion of the injured digits and the function of the aficted hand. Tese injuries afect over 140,000 full-time employees in the United States alone, losing over one million workdays annually1. Furthermore, adhesion formation is not limited to hand surgery, but is considered a substantial postoperative complication in all surgical procedures. While the incidence and severity of postoperative adhesions vary between surgical specialties2, identifying the mechanisms of adhesions and designing novel pharmacological or biological therapies to mitigate them remain as unmet clinical needs. Adhesions in tendon3,4 as well as throughout the body have been causatively associated with Transforming Growth Factor Beta 1 (TGF-β1)5,6. TGF-β1 stimulates myofbroblast activation, leading to increased matrix syn- thesis and decreased matrix remodeling7. Studies on the healing of fexor digitorum profundus (FDP) tendon in chicken demonstrated that TGF-β1 is highly expressed throughout the early healing period, particularly in the peritendinous region, as evidenced by immunohistochemistry8. Tus, TGF-β1 has been identifed as a therapeu- tic target for adhesions. Neutralizing antibodies to TGF-β1 have been shown to reduce rat fexor tendon adhe- sions following transection3, and TGF-β1 inhibitors such as mannose-6-phosphate also improve postoperative range of motion (ROM) in rabbit zone II fexor tendons9. Tese treatments, however, reduce tendon mechanical strength, especially at higher doses3,9. We have recently demonstrated that disruption of canonical TGF-β1 sign- aling in Smad3−/− mice reduced fexor tendon adhesions and improved tendon gliding, due to reduced extracel- lular matrix (ECM) deposition, but led to compromised biomechanical properties with a signifcant reduction in repair strength4. Tus, the indispensable reparative efects of TGF-β1 limit the applicability of TGF-β1-directed therapeutics in load bearing tendons. In lieu of this approach, we hypothesized that canonical TGF-β1 signaling 1Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA. 2Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA. 3Department of Orthopedics, University of Rochester Medical Center, Rochester, NY, USA. Correspondence and requests for materials should be addressed to H.A.A. (email: [email protected]) SCIENTIFIC REPORTS | (2018) 8:5810 | DOI:10.1038/s41598-018-24144-1 1 www.nature.com/scientificreports/ Figure 1. TGF-β1 and PAI-1 are ubiquitous in fbrotic human tendon tissue. Immunohistochemical (IHC) staining of normal human tendon (A and C) and fbrotic Dupuytren’s contracture tissue (B and D) against TGF- β1 and PAI-1. Brown staining in B and D indicates increased TGF-β1 and PAI-1, respectively. induces downstream mediators of fbrosis, which may include novel therapeutic targets. One such target is the protease suppressor, plasminogen activator inhibitor 1 or PAI-1. Activation of canonical TGF-β1 directly upregulates PAI-110,11. As a direct inhibitor of both tissue- and urokinase-type plasminogen activators (tPA and uPA, respectively), PAI-1 acts as a master regulator of plasmin activity, thereby regulating fbrinolysis and plasmin-mediated activation of matrix metalloproteinases (MMP)11. As a repressor of MMP activity, increased PAI-1 has been implicated in major organ fbrotic conditions includ- ing skin, liver, kidney, and lung12–18 and strategies to abrogate its efects have demonstrated preclinical proof of efcacy19,20. However, formal evaluation of the role of PAI-1 in tendon adhesions following injury has not been previously explored. Te objective of this study was to assess efects of PAI-1 therapeutic inhibition on fexor tendon healing using a zone II injury to the deep digital fexor tendon in mice. We frst utilized a PAI-1 knockout (PAI-1 KO) mouse to evaluate the efects of global gene deletion of Serpine1 (which encodes for PAI-1) on fexor tendon healing over time compared to C57Bl6/J (WT) controls. Next, we used siRNA approaches to knockdown Serpine1 to test whether this approach reverses PAI-1 suppression of protease activity in tendon fbroblast cultures in vitro. Finally, we treated fexor tendon injuries in WT mice using a nanoparticle-mediated localized siRNA delivery strategy21,22 to inhibit Serpine1 gene expression in vivo and evaluate repair tissue remodeling. Results PAI-1 is abundant in fbrotic tendon tissue. We sought to frst determine the abundance of TGF-β1 and PAI-1 in tendon fbrosis. To that end, we performed immunohistochemistry staining on fbrotic Dupuytren’s tissue from human fexor tendons and observed ubiquitous levels of TGF-β1 and PAI-1 (Fig. 1), which is con- sistent with published reports implicating this pathway in mediating the fbrotic traits of Dupuytren’s disease in tendon23. We also observed that TGF-β1 and PAI-1 are abundant in the healing and adhesion tissue developed 14 days following zone II injury to the deep digital fexor tendon in the hind paw of C57Bl/6 J WT mice (Fig. 2). PAI-1 deficiency reduces healing tendon adhesions to subcutaneous tissues. The effects of gene deletion of Serpine1 on fexor tendon adhesions were evaluated histomorphometrically over time up to 56 days post injury (dpi) in WT and PAI-1 KO mice. Te fexor tendons of the middle digits of the hind paws in both murine strains were partially lacerated between the metatarsophalangeal and the proximal interphalan- geal joints to simulate a zone II fexor tendon injury in the human hand (Supplementary Figure S1). To reduce dehydration-related shrinkage and to enable a more accurate histomorphometric quantifcation, we used a water-based mounting medium to coverslip hematoxylin-stained axial sections, allowing for excellent preserva- tion of tissue morphology as well as sufcient contrast to distinguish between normal and injured tendons, pul- leys, and subcutaneous tissues (Supplementary Figure S2). Qualitative assessment of hematoxylin-stained axial tendon sections (Fig. 3A) in both mouse strains demonstrated a thickening of the synovial sheath with increased cellularity in the extratendinous region surrounding the tendon as early as 3 and 7 dpi. Signifcant adhesions that compromised the gliding space and obscured the margins between the tendon and extratendinous tissues were observed by 7 dpi. In the proliferative/granulation phases of healing between 14 and 28 dpi, increased cell SCIENTIFIC REPORTS | (2018) 8:5810 | DOI:10.1038/s41598-018-24144-1 2 www.nature.com/scientificreports/ Figure 2. TGF-β1 and PAI-1 are abundant in injured mouse fexor tendon adhesions. Sagittal sections of uninjured (A–C) and Zone II partially-lacerated (D–F) deep digital fexor tendons at 14 dpi. Sections are stained using hematoxylin and eosin (E and H) and antibodies against TGF-β1 and PAI-1. Arrows indicate the laceration site. Box in D shows the adhesions surrounding the injured tendon (magnifed in E and F). Asterisks in E and F highlight the intense brown staining indicative of increased TGF-β1 and PAI-1, respectively, in the adhesions (scar tissue). B = bone, T = tendon, and S = skin. numbers and initial matrix deposition were observed in the healing tendon in both mouse strains. Between 28 and 56 dpi, the healing tendon began to undergo contraction and remodeling and the gliding space between the tendon and subcutaneous tissues exhibited signs of recovery in both mouse strains. A quantitative histomorpho- metric assessment of fexor tendon size, adhesions, sheath space and tendon cellularity was carried out systemat- ically over 5 axial section levels spanning
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