Pifithrin-α, an inhibitor of p53 transactivation, alters the inflammatory process and delays tendon healing following acute injury

2007 ◽  
Vol 292 (1) ◽  
pp. R321-R327 ◽  
Author(s):  
David Marsolais ◽  
Claude H. Côté ◽  
Jérôme Frenette
Keyword(s):  
Extracellular Matrix ◽  
Inflammatory Process ◽  
Tendon Repair ◽  
Tendon Healing ◽  
Tendon Injury ◽  
Acute Injury ◽  
Inflammatory Phase ◽  
Load To Failure ◽  
Transcription Factor P53

Transcription factor p53, which was initially associated with cancer, has now emerged as an important regulator of inflammation and extracellular matrix homeostasis, two processes highly relevant to tendon repair. The goal of this study was to evaluate the effect of a p53 transactivation inhibitor, namely, pifithrin-α, on the pathophysiological sequence following collagenase-induced tendon injury. Administration of pifithrin-α during the inflammatory phase reduced the accumulation of neutrophils and macrophages by 30 and 40%, respectively, on day 3 postinjury. Pifithrin-α failed to reduce the percentage of apoptotic cells following collagenase injection but delayed functional recovery. In uninjured Achilles tendons, pifithrin-α increased metalloprotease activity 2.4-fold. Accordingly, pifithrin-α reduced the collagen content in intact tendons as well as in injured tendons 7 days posttrauma compared with placebo. The effect of pifithrin-α on load to failure and stiffness was also evaluated. The administration of pifithrin-α during the inflammatory phase did not significantly decrease the functional deficit 3 days posttrauma. More importantly, load to failure and stiffness were significantly decreased in the pifithrin-α group from day 7 to day 28 compared with placebo. Overall, our results suggest that administration of pifithrin-α alters the inflammatory process and delays tendon healing. The present findings also support the concept that p53 can regulate extracellular matrix homeostasis in vivo.

Effect of rhPDGF-BB-Coated Sutures on Tendon Healing in a Rat Model: A Histological and Biomechanical Study

2011 ◽  
Author(s):  
S. Cummings ◽  
J. Dines ◽  
C. K. Hee ◽  
H. K. Kestler ◽  
C. M. Roden ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tissue Repair ◽  
Tendon Repair ◽  
Tendon Healing ◽  
Tendon Injury ◽  
Biomechanical Study ◽  
Growth Factor Delivery ◽  
Delivery Method

Delivering growth factors to the site of injury using a coated suture delivery method has been investigated recently as a means to augment tissue repair [1]. This is a practical approach for growth factor delivery, as sutures are the method of choice for most orthopaedic surgeons for soft tissue repairs. One advantage of growth factor-coated sutures in tendon repair is the potential to accelerate healing in vivo, thereby improving the outcome of the repair. In particular, platelet-derived growth factor-BB (PDGF-BB) is a well characterized wound healing protein known to be chemotactic and mitogenic for cells of mesenchymal origin, including tenocytes, and has been shown to improve healing when applied to animal models of tendon injury [2,3]. The aim of this study was to compare the quality of the tendon repair at four weeks post treatment with sutures coated with varying concentrations of rhPDGF-BB, relative to buffer-coated suture repairs.

scholarly journals Short-Duration RAGE Antagonism Transiently Disrupts Tendon Homeostasis and does not Alter Diabetic Tendon Healing

2021 ◽  
Author(s):  
Anne EC Nichols ◽  
Samantha N Muscat ◽  
Alayna E Loiselle
Keyword(s):  
Advanced Glycation Endproducts ◽  
Healing Process ◽  
Tendon Repair ◽  
Tendon Healing ◽  
Type Ii Diabetes Mellitus ◽  
Tendon Injury ◽  
Acute Injury ◽  
Molecular Profile ◽  
Diet Induced Obesity ◽  
Increased Risk

Obesity and type II Diabetes Mellitus (T2DM) have substantial pathological effects on tendon homeostasis, including loss of collagen organization and increased risk of tendon rupture. Moreover, following rupture or acute injury, the healing process is impaired by T2DM. We have previously demonstrating that restoring normal metabolic function in a murine model of obesity/ T2DM is insufficient to blunt or reverse the progression of diabetic tendinopathy, indicating the need for identification of novel therapeutic approaches to both maintain tendon homeostasis, and to improve the healing process. RAGE, the Receptor for Advanced Glycation Endproducts has been implicated as a key driver of several diabetic pathologies. We have demonstrated that pharmacological antagonism of RAGE is sufficient to partially improve tendon healing in non-diabetic animals. Therefore, in the current study we tested the efficacy of blunted RAGE signaling, via treatment with a RAGE Antagonist Peptide (RAP), to improve tendon healing in the context of T2DM. While our study did not find a beneficial effect of short-term RAP treatment on the healing process of T2DM mice, we did identify several important challenges brought about by this model of diet-induced obesity and T2DM. Both high fat (HFD) and low fat diet (LFD) feeding shifted the temporal molecular profile of healing compared to standard laboratory chow fed mice. Moreover, RAP treatment resulted in a transient disruption in homeostasis in the contralateral control tendons of both HFD and LFD mice, and this was due to a potential interaction with the systemic response to tendon injury as this response was not observed in HFD and LFD fed mice that did not undergo tendon repair surgery. Collectively, these data highlight the complications associated with models of diet induced obesity, and the lean control diets that should be considered in future studies.

scholarly journals Molecular Mechanisms of Fetal Tendon Regeneration Versus Adult Fibrous Repair

2021 ◽  
Vol 22 (11) ◽  
pp. 5619
Author(s):  
Iris Ribitsch ◽  
Andrea Bileck ◽  
Alexander D. Aldoshin ◽  
Maciej M. Kańduła ◽  
Rupert L. Mayer ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Molecular Mechanisms ◽  
Unmet Need ◽  
Tendon Healing ◽  
Tendon Injury ◽  
Inflammatory Factors ◽  
Large Animal ◽  
Post Injury ◽  
Tendon Regeneration ◽  
Large Animal Models

Tendinopathies are painful, disabling conditions that afflict 25% of the adult human population. Filling an unmet need for realistic large-animal models, we here present an ovine model of tendon injury for the comparative study of adult scarring repair and fetal regeneration. Complete regeneration of the fetal tendon within 28 days is demonstrated, while adult tendon defects remained macroscopically and histologically evident five months post-injury. In addition to a comprehensive histological assessment, proteome analyses of secretomes were performed. Confirming histological data, a specific and pronounced inflammation accompanied by activation of neutrophils in adult tendon defects was observed, corroborated by the significant up-regulation of pro-inflammatory factors, neutrophil attracting chemokines, the release of potentially tissue-damaging antimicrobial and extracellular matrix-degrading enzymes, and a response to oxidative stress. In contrast, secreted proteins of injured fetal tendons included proteins initiating the resolution of inflammation or promoting functional extracellular matrix production. These results demonstrate the power and relevance of our novel ovine fetal tendon regeneration model, which thus promises to accelerate research in the field. First insights from the model already support our molecular understanding of successful fetal tendon healing processes and may guide improved therapeutic strategies.

Gross and Histological Analysis of Healing After Dog Flexor Tendon Repair with the Teno Fix™ Device

2006 ◽  
Vol 31 (5) ◽  
pp. 524-529 ◽  
Author(s):  
B. W. SU ◽  
F. J. RAIA ◽  
H. M. QUITKIN ◽  
M. PARISIEN ◽  
R. J. STRAUCH ◽  
...  
Keyword(s):  
Flexor Tendon ◽  
Weight Bearing ◽  
Tendon Repair ◽  
Tendon Healing ◽  
Full Weight Bearing ◽  
Cast Immobilization ◽  
Flexor Tendon Repair ◽  
The Common ◽  
Flexor Digitorum

The purpose of this study was to examine the in vivo characteristics of the stainless-steel Teno Fix™ device used for flexor tendon repair. The common flexor digitorum superficialis tendon was transected in 16 dogs and repaired with the device. The animals were euthanized at 3, 6, or 12 weeks postoperatively. Difficulties with cast immobilization led nine of 16 animals to be full weight bearing too early, leading to rupture of their repairs. The seven tendons with successful primary repairs (gap <2 mm) underwent histological examination. This in vivo study demonstrates that use of the Teno Fix™ in “suture” of dog flexor tendons did not lead to scarring at the tendon surface, does not cause an inflammatory reaction within the tendon and does not interfere with tendon healing.

Hypoxia promotes tenocyte differentiation of mesenchymal stem cells

2020 ◽  
Author(s):  
Guanyin Chen ◽  
wangqian zhang ◽  
Jintao Gu ◽  
Yuan Gao ◽  
Lei He ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Patellar Tendon ◽  
Tendon Repair ◽  
Clinical Results ◽  
Tendon Injury ◽  
Tenogenic Differentiation ◽  
Tgf Β1

Abstract Background: Tendon injury is a common but tough medical problem. Unsatisfactory clinical results have been reported in tendon repair using mesenchymal stem cells (MSCs) therapy, creating a need for a better strategy to induce MSCs to tenogenic differentiation. This study was designed to investigate the role of hypoxia in the tenogenic differentiation of MSCs in vitro and in vivo and to compare the tenogenic differentiation capacities of different MSCs under hypoxia condition in vitro. Methods: Adipose tissue-derived MSCs (AMSCs) and bone marrow-derived MSCs (BMSCs) were isolated and characterized by the expression of MSC-specific markers and tri-lineage differentiation. The expression of hypoxia induced factor-1 alpha (Hif-1α) and the proliferation of AMSCs and BMSCs were examined in order to confirm the establishment of hypoxia condition. qRT-PCR, western blot, and immunofluorescence staining were used to evaluate the expression of tendon-associated marker Col-1a1, Col-3a1, Dcn, and Tnmd in AMSCs and BMSCs under hypoxia and/or Tgf-β1 condition. In vivo, a patellar tendon injury model was established. Normoxic and hypoxic BMSCs were cultured and implanted. Histological, biomechanical and transmission electron microscopy analyses were performed to assess the improved healing effect of hypoxic BMSCs on tendon injury. Results: Hypoxia remarkably increased the expression of Hif-1α and the proliferation of AMSCs and BMSCs. Our in vitro results detected that hypoxia not only promoted a significant increase in tenogenic markers in both AMSCs and BMSCs compared with the normoxia group, but also showed higher inductility compared with Tgf-β1. In addition, hypoxic BMSCs exhibited higher potential of tenogenic differentiation than hypoxic AMSCs. Our in vivo results demonstrated that hypoxic BMSCs possessed better histological and biomechanical properties than those of normoxic BMSCs, as evidenced by histological scores, quantitative analysis of immunohistochemical staining for Col-1a1 and Tnmd, the range and average of collagen fibril diameters and patellar tendon biomechanical tests. Conclusions: These findings suggested that hypoxia may be a practical and reliable strategy to induce tenogenic differentiation of BMSCs for tendon repair and could enhance the effectiveness of MSCs therapy in treating tendon injury.

scholarly journals Hypoxia-Induced Mesenchymal Stem Cells Exhibit Stronger Tenogenic Differentiation Capacities and Promote Patellar Tendon Repair in Rabbits

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Guanyin Chen ◽  
Wangqian Zhang ◽  
Kuo Zhang ◽  
Shuning Wang ◽  
Yuan Gao ◽  
...  
Keyword(s):  
Patellar Tendon ◽  
Tendon Repair ◽  
Biomechanical Properties ◽  
Clinical Results ◽  
Medical Problem ◽  
Tendon Injury ◽  
Tenogenic Differentiation ◽  
Tgf Β1

Tendon injury is a common but tough medical problem. Unsatisfactory clinical results have been reported in tendon repair using mesenchymal stem cell (MSC) therapy, creating a need for a better strategy to induce MSCs to tenogenic differentiation. This study was designed to examine the effect of hypoxia on the tenogenic differentiation of different MSCs and their tenogenic differentiation capacities under hypoxia condition in vitro and to investigate the in vivo inductility of hypoxia in tenogenesis. Adipose tissue-derived MSCs (AMSCs) and bone marrow-derived MSCs (BMSCs) were isolated and characterized. The expression of hypoxia-induced factor-1 alpha (Hif-1α) was examined to confirm the establishment of hypoxia condition. qRT-PCR, western blot, and immunofluorescence staining were used to evaluate the expression of tendon-associated marker Col-1a1, Col-3a1, Dcn, and Tnmd in AMSCs and BMSCs under hypoxia condition, compared with Tgf-β1 induction. In vivo, a patellar tendon injury model was established. Normoxic and hypoxic BMSCs were cultured and implanted. Histological, biomechanical, and transmission electron microscopy analyses were performed to assess the improved healing effect of hypoxic BMSCs on tendon injury. Our in vitro results showed that hypoxia remarkably increased the expression of Hif-1α and that hypoxia not only promoted a significant increase in tenogenic markers in both AMSCs and BMSCs compared with the normoxia group but also showed higher inductility compared with Tgf-β1. In addition, hypoxic BMSCs exhibited higher potential of tenogenic differentiation than hypoxic AMSCs. Our in vivo results demonstrated that hypoxic BMSCs possessed better histological and biomechanical properties than normoxic BMSCs, as evidenced by histological scores, patellar tendon biomechanical parameters, and the range and average of collagen fibril diameters. These findings suggested that hypoxia may be a practical and reliable strategy to induce tenogenic differentiation of BMSCs for tendon repair and could enhance the effectiveness of MSCs therapy in treating tendon injury.

Therapeutic Mechanisms of Human Adipose-Derived Mesenchymal Stem Cells in a Rat Tendon Injury Model

2017 ◽  
Vol 45 (6) ◽  
pp. 1429-1439 ◽  
Author(s):  
Sang Yoon Lee ◽  
Bomi Kwon ◽  
Kyoungbun Lee ◽  
Young Hoon Son ◽  
Sun G. Chung
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tendon Healing ◽  
Collagen Type I ◽  
Tendon Injury ◽  
Cell Group ◽  
Type I ◽  
Injury Model ◽  
Human Specific

Background: Although survival of transplanted stem cells in vivo and differentiation of stem cells into tenocytes in vitro have been reported, there have been no in vivo studies demonstrating that mesenchymal stem cells (MSCs) could secrete their own proteins as differentiated tenogenic cells. Purpose/Hypothesis: Using a xenogeneic MSC transplantation model, we aimed to investigate whether MSCs could differentiate into the tenogenic lineage and secrete their own proteins. The hypothesis was that human MSCs would differentiate into the human tenogenic lineage and the cells would be able to secrete human-specific proteins in a rat tendon injury model. Study Design: Controlled laboratory study. Methods: The Achilles tendons of 57 Sprague Dawley rats received full-thickness rectangular defects. After the modeling, the defective tendons were randomly assigned to 3 groups: (1) cell group, implantation with human adipose-derived mesenchymal stem cells (hASCs) and fibrin glue (106 cells in 60 μL); (2) fibrin group, implantation with fibrin glue and same volume of cell media; and (3) sham group, identical surgical procedure without any treatment. Gross observation and biomechanical, histopathological, immunohistochemistry, and Western blot analyses were performed at 2 and 4 weeks after modeling. Results: hASCs implanted into the defective rat tendons were viable for 4 weeks as detected by immunofluorescence staining. Tendons treated with hASCs showed better gross morphological and biomechanical recovery than those in the fibrin and sham groups. Furthermore, the expression of both human-specific collagen type I and tenascin-C was significantly higher in the cell group than in the other 2 groups. Conclusion: Transplantation of hASCs enhanced rat tendon healing biomechanically. hASCs implanted into the rat tendon defect model survived for at least 4 weeks and secreted human-specific collagen type I and tenascin-C. These findings suggest that transplanted MSCs may be able to differentiate into the tenogenic lineage and contribute their own proteins to tendon healing. Clinical Relevance: In tendon injury, MSCs can enhance tendon healing by secreting their own protein and have potential as a therapeutic option in human tendinopathy.

Analysis of Collagen Fiber Organization in Mouse Achilles Tendon Using High-Frequency Ultrasound Imaging

2013 ◽  
Author(s):  
Corinne N. Riggin ◽  
Joseph J. Sarver ◽  
Benjamin R. Freedman ◽  
Stephen J. Thomas ◽  
Louis J. Soslowsky
Keyword(s):  
Achilles Tendon ◽  
Functional Performance ◽  
Tendon Healing ◽  
Tendon Injury ◽  
High Frequency Ultrasound ◽  
Medical Expense ◽  
Collagen Organization ◽  
Tendon Ruptures ◽  
And Function

Achilles tendon ruptures are traumatic injuries that frequently occur in active individuals and result in significant medical expense. Common techniques for assessing outcomes of surgical repair and rehabilitation rely heavily on patient-based measures of pain and function. While these measures can provide evidence for recovery of functional performance, they do not directly assess tendon healing which, if insufficient, can lead to re-rupture. The clinical evaluation of collagen organization following Achilles tendon injury may provide a more accurate measure of healing than traditional, functional performance tests. It has been shown that changes in collagen organization precede and correlate with changes in mechanical properties in tendons [1–3] and that load and injury effect collagen organization [4–6]. Ultimately, if collagen organization could be quantified in vivo, it would represent a powerful, diagnostic tool to measure the progression of tendon healing, as well as to monitor damage accumulation due to injury.

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