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1
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Quam V. Evidence Related to the Effects of Intralesional/Intrasynovial Corticosteroids on Tendon/Ligament Homeostasis and Healing. Vet Clin North Am Equine Pract 2025:S0749-0739(25)00024-0. [PMID: 40425387 DOI: 10.1016/j.cveq.2025.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2025] Open
Abstract
Inflammation plays a role in acute and chronic equine tendon/ligament injury; anti-inflammatories are often indicated. Local corticosteroids provide consistent and profound short-term effects on pain and inflammation across species. However, there is no demonstrated benefit in the long term, and complications can occur. Alternative biologic anti-inflammatory treatments are available and should be used in horses at risk of complications. Nonetheless, corticosteroids remain an affordable and effective anti-inflammatory that, with continued research, may be indicated on a case-by-case basis as part of a multimodal treatment plan.
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Affiliation(s)
- Vivian Quam
- Littleton Equine Medical Center, 8025 South Santa Fe Drive, Littleton, CO 80120, USA.
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2
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Xu Z, Hou W, Zhang T, Chen R, Skutella T. Exploring molecular and cellular signaling pathways: Unraveling the pathogenesis of tendinopathy. J Orthop Translat 2025; 51:298-311. [PMID: 40201708 PMCID: PMC11978293 DOI: 10.1016/j.jot.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 01/09/2025] [Accepted: 02/05/2025] [Indexed: 04/10/2025] Open
Abstract
Despite the long healing duration of tendon injuries, the outcomes of repairs are frequently suboptimal, resulting in persistent pain and reduced functionality. Current clinical approaches to tendinopathy are primarily symptomatic, encompassing nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroid injections, physical therapies, surgical interventions, loading programs, and pain management. Yet, these treatments have protracted timelines and their efficacy remains uncertain. This uncertainty stems largely from an incomplete understanding of tendinopathy's pathogenesis. Unraveling the mechanisms behind tendinopathy is essential for devising novel therapeutic strategies. In this context, this review systematic reviewed more recent cellular and molecular literature in tendinopathy, in order to summarize the up-to-date advancements including the structure and composition of healthy tendons, the pathophysiological changes in tendinopathy, the molecular pathways implicated in various forms of the condition, and current effective treatment methods. This review not only aims to offer insights but also to inspire further investigation into the mechanisms and clinical management of tendinopathy. The translational potential of this article A deficient understanding of the molecular mechanisms hampers the advancement of therapeutic strategies and drug development. Consequently, an in-depth examination of these molecular mechanisms is essential for comprehending the etiology of tendinopathy and for devising effective clinical management strategies.
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Affiliation(s)
- Zihan Xu
- Department of Neuroanatomy, Group for Regeneration and Reprogramming, Institute for Anatomy and Cell Biology, Medical Faculty, Heidelberg University, 69120, Heidelberg, Germany
| | - Wenjing Hou
- Department of Neuroanatomy, Group for Regeneration and Reprogramming, Institute for Anatomy and Cell Biology, Medical Faculty, Heidelberg University, 69120, Heidelberg, Germany
| | - Tao Zhang
- Department of Neuroanatomy, Group for Regeneration and Reprogramming, Institute for Anatomy and Cell Biology, Medical Faculty, Heidelberg University, 69120, Heidelberg, Germany
| | - Rui Chen
- Department of Reproductive Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, China
| | - Thomas Skutella
- Department of Neuroanatomy, Group for Regeneration and Reprogramming, Institute for Anatomy and Cell Biology, Medical Faculty, Heidelberg University, 69120, Heidelberg, Germany
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3
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Stauber T, Moschini G, Hussien AA, Jaeger PK, De Bock K, Snedeker JG. Il-6 signaling exacerbates hallmarks of chronic tendon disease by stimulating reparative fibroblasts. eLife 2025; 12:RP87092. [PMID: 39918402 PMCID: PMC11805502 DOI: 10.7554/elife.87092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2025] Open
Abstract
Tendinopathies are debilitating diseases currently increasing in prevalence and associated costs. There is a need to deepen our understanding of the underlying cell signaling pathways to unlock effective treatments. In this work, we screen cell signaling pathways in human tendinopathies and find positively enriched IL-6/JAK/STAT signaling alongside signatures of cell populations typically activated by IL-6 in other tissues. In human tendinopathic tendons, we also confirm the strong presence and co-localization of IL-6, IL-6R, and CD90, an established marker of reparative fibroblasts. To dissect the underlying causalities, we combine IL-6 knock-out mice with an explant-based assembloid model of tendon damage to successfully connect IL-6 signaling to reparative fibroblast activation and recruitment. Vice versa, we show that these reparative fibroblasts promote the development of tendinopathy hallmarks in the damaged explant upon IL-6 activation. We conclude that IL-6 activates tendon fibroblast populations which then initiate and deteriorate tendinopathy hallmarks.
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Affiliation(s)
- Tino Stauber
- Laboratory for Orthopedic Biomechanics, University Hospital Balgrist and ETH ZurichZurichSwitzerland
| | - Greta Moschini
- Laboratory for Orthopedic Biomechanics, University Hospital Balgrist and ETH ZurichZurichSwitzerland
- Laboratory of Exercise and Health Department of Health Sciences and Technology (D-HEST) ETH Zurich, Swiss Federal Institute of TechnologyZurichSwitzerland
| | - Amro A Hussien
- Laboratory for Orthopedic Biomechanics, University Hospital Balgrist and ETH ZurichZurichSwitzerland
| | - Patrick Klaus Jaeger
- Laboratory for Orthopedic Biomechanics, University Hospital Balgrist and ETH ZurichZurichSwitzerland
| | - Katrien De Bock
- Laboratory of Exercise and Health Department of Health Sciences and Technology (D-HEST) ETH Zurich, Swiss Federal Institute of TechnologyZurichSwitzerland
| | - Jess G Snedeker
- Laboratory for Orthopedic Biomechanics, University Hospital Balgrist and ETH ZurichZurichSwitzerland
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Morya VK, Shahid H, Lang J, Kwak MK, Park SH, Noh KC. Advancements in Therapeutic Approaches for Degenerative Tendinopathy: Evaluating Efficacy and Challenges. Int J Mol Sci 2024; 25:11846. [PMID: 39519397 PMCID: PMC11545934 DOI: 10.3390/ijms252111846] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/31/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024] Open
Abstract
Degenerative tendinopathy results from the accumulation of minor injuries following unsuccessful tendon repair during acute tendon injuries. The process of tendon repair is prolonged and varies between individuals, making it susceptible to reinjury. Moreover, treating chronic tendinopathy often requires expensive and extensive rehabilitation, along with a variety of combined therapies to facilitate recovery. This condition significantly affects the quality of life of affected individuals, underscoring the urgent need for more efficient and cost-effective treatment options. Although traditional treatments have improved significantly and are being used as substitutes for surgical interventions, the findings have been inconsistent and conflicting. This review aims to clarify these issues by exploring the strengths and limitations of current treatments as well as recent innovations in managing various forms of degenerative tendinopathy.
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Affiliation(s)
- Vivek Kumar Morya
- Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si 18450, Republic of Korea; (V.K.M.); (J.L.)
- School of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Hamzah Shahid
- Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si 18450, Republic of Korea; (V.K.M.); (J.L.)
- School of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Jun Lang
- Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si 18450, Republic of Korea; (V.K.M.); (J.L.)
- School of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Mi Kyung Kwak
- Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si 18450, Republic of Korea; (V.K.M.); (J.L.)
- School of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Sin-Hye Park
- Department of Food Science & Nutrition, Hallym University, Chuncheon 24252, Republic of Korea
| | - Kyu-Cheol Noh
- School of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
- Hallym University Sacred Heart Hospital, Anyang-si 14068, Republic of Korea
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Nilsson N, Alim MDA, Dietrich-Zagonel F, Concaro S, Brorsson A, Nilsson Helander K, Eliasson P. The Delayed Presentation of Achilles Tendon Ruptures Is Associated With Marked Alterations in the Gene Expression of COL1A1, MMPs, TIMPs, and IL-6. Am J Sports Med 2024; 52:164-173. [PMID: 38164679 DOI: 10.1177/03635465231212669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
BACKGROUND Both acute and chronic Achilles tendon ruptures are affected by alterations in the extracellular matrix during the healing process of the tendon. Yet, these alterations in gene expression patterns are not well characterized. PURPOSE To characterize temporal and spatial differences in gene expression patterns after an Achilles tendon rupture and to evaluate if cells from chronic Achilles tendon ruptures have the same ability to form new tendon tissue (tendon constructs) as healthy tendon cells. STUDY DESIGN Controlled laboratory study. METHODS A total of 35 patients with surgically treated Achilles tendon ruptures were included in the study and divided into 3 groups: acute (<4 weeks), short-term chronic (1-6 months), and long-term chronic (>6 months). Biopsy specimens were collected during surgical repair and were used to analyze the gene expression within the different groups and to compare mRNA levels in the proximal and distal tendon ends. A complementary in vitro experiment was performed to evaluate if cells from chronic Achilles tendon ruptures can form tendon constructs. RESULTS The mRNA levels for COL1A1 and COL3A1 were significantly higher in the short-term chronic group compared with the acute group (P < .05). Both MMP-1 and MMP-13 had the highest mRNA levels in the acute group (P < .01) compared with the long-term chronic group, while MMP-2 had the highest mRNA level in the short-term chronic group. Significant differences between the proximal and distal tendon ends were only detected for the monocyte and macrophage marker CD163 (P < .05), which was more expressed proximally. Cells extracted from chronic Achilles tendon ruptures displayed a similar ability and effectiveness to form tendon constructs as healthy tendon cells. CONCLUSION A high collagenase gene activity after an Achilles tendon rupture indicated possible rapid matrix degradation in the acute phase. Chronic ruptures appeared to initiate the healing process even before treatment, indicated by the higher expression of collagen in the short-term chronic group. Cells from chronic Achilles tendon ruptures also displayed an ability to form new tendon tissue in vitro. CLINICAL RELEVANCE The study shows a rapid increase in collagenase gene expression, which could lead to matrix degradation that continues for months after an Achilles tendon rupture.
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Affiliation(s)
- Niklas Nilsson
- Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Orthopaedics, Sahlgrenska University Hospital, Mölndal, Sweden
| | - M D Abdul Alim
- Division of Orthopaedics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Franciele Dietrich-Zagonel
- Division of Orthopaedics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Sebastian Concaro
- Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Orthopaedics, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Annelie Brorsson
- Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- IFK Kliniken Rehab, Gothenburg, Sweden
| | - Katarina Nilsson Helander
- Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Orthopaedics, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Pernilla Eliasson
- Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Division of Orthopaedics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
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Nemska S, Serio S, Larcher V, Beltrame G, Portinaro NM, Bang ML. Whole Genome Expression Profiling of Semitendinosus Tendons from Children with Diplegic and Tetraplegic Cerebral Palsy. Biomedicines 2023; 11:2918. [PMID: 38001919 PMCID: PMC10669597 DOI: 10.3390/biomedicines11112918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/17/2023] [Accepted: 10/26/2023] [Indexed: 11/26/2023] Open
Abstract
Cerebral palsy (CP) is the most common movement disorder in children, with a prevalence ranging from 1.5 to 4 per 1000 live births. CP is caused by a non-progressive lesion of the developing brain, leading to progressive alterations of the musculoskeletal system, including spasticity, often leading to the development of fixed contractures, necessitating tendon lengthening surgery. Total RNA-sequencing analysis was performed on semitendinosus tendons from diplegic and tetraplegic CP patients subjected to tendon lengthening surgery compared to control patients undergoing anterior cruciate ligament reconstructive surgery. Tetraplegic CP patients showed increased expression of genes implicated in collagen synthesis and extracellular matrix (ECM) turnover, while only minor changes were observed in diplegic CP patients. In addition, tendons from tetraplegic CP patients showed an enrichment for upregulated genes involved in vesicle-mediated transport and downregulated genes involved in cytokine and apoptotic signaling. Overall, our results indicate increased ECM turnover with increased net synthesis of collagen in tetraplegic CP patients without activation of inflammatory and apoptotic pathways, similar to observations in athletes where ECM remodeling results in increased tendon stiffness and tensile strength. Nevertheless, the resulting increased tendon stiffness is an important issue in clinical practice, where surgery is often required to restore joint mobility.
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Affiliation(s)
- Simona Nemska
- Milan Unit, Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), 20138 Milan, Italy; (S.N.); (S.S.)
- IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Simone Serio
- Milan Unit, Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), 20138 Milan, Italy; (S.N.); (S.S.)
- IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Veronica Larcher
- Institute of Cardiovascular Regeneration, Goethe University, 60590 Frankfurt, Germany;
| | - Giulia Beltrame
- Residency Program in Orthopedics and Traumatology, University of Milan, 20100 Milan, Italy;
| | - Nicola Marcello Portinaro
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy;
- Department of Pediatric Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20100 Milan, Italy
| | - Marie-Louise Bang
- Milan Unit, Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), 20138 Milan, Italy; (S.N.); (S.S.)
- IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
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Nguyen PK, Hall K, Holt I, Kuo CK. Recombinant lysyl oxidase effects on embryonic tendon cell phenotype and behavior. J Orthop Res 2023; 41:2175-2185. [PMID: 37365857 PMCID: PMC11487497 DOI: 10.1002/jor.25655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 05/11/2023] [Accepted: 06/21/2023] [Indexed: 06/28/2023]
Abstract
Lysyl oxidase (LOX) plays an important role in the elaboration of tendon mechanical properties during embryonic development by mediating enzymatic collagen crosslinking. We previously showed recombinant LOX (rLOX) treatment of developing tendon significantly increased LOX-mediated collagen crosslink density to enhance tendon mechanical properties at different stages of tissue formation. Working toward the future development of rLOX-based therapeutic strategies to enhance mechanical properties of tendons that are compromised, such as after injury or due to abnormal development, this study characterized the direct effects of rLOX treatment on embryonic tendon cells from different stages of tissue formation. Tendon cell morphology, proliferation rate, proliferative capacity, and metabolic activity were not affected by rLOX treatment. Tenogenic phenotype was stable with rLOX treatment, reflected by no change in cell morphology or tendon marker messenger RNA (mRNA) levels assessed by reverse-transcription polymerase chain reaction. Collagen mRNA levels also remained constant. Matrix metalloproteinase-9 expression levels were downregulated in later stage tendon cells, but not in earlier stage cells, whereas enzyme activity levels were undetected. Bone morphogenetic protein-1 (BMP-1) expression was upregulated in earlier stage tendon cells, but not in later stage cells. Furthermore, BMP-1 activity was unchanged when intracellular LOX enzyme activity levels were upregulated in both stage cells, suggesting exogenous rLOX may have entered the cells. Based on our data, rLOX treatment had minimal effects on tendon cell phenotype and behaviors. These findings will inform future development of LOX-focused treatments to enhance tendon mechanical properties without adverse effects on tendon cell phenotype and behaviors.
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Affiliation(s)
- Phong K. Nguyen
- Department of Biomedical Engineering, University of Rochester, NY
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY
- Fischell Department of Bioengineering, University of Maryland, College Park, MD
| | - Kaitlyn Hall
- Fischell Department of Bioengineering, University of Maryland, College Park, MD
| | - Iverson Holt
- Fischell Department of Bioengineering, University of Maryland, College Park, MD
| | - Catherine K. Kuo
- Department of Biomedical Engineering, University of Rochester, NY
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY
- Fischell Department of Bioengineering, University of Maryland, College Park, MD
- Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD
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8
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Williams S, Ligas C, Oloff L, Klein TE. The Role of Epigenomics in Mapping Potential Precursors for Foot and Ankle Tendinopathy: A Systematic Review. Foot Ankle Spec 2023; 16:446-454. [PMID: 37165881 DOI: 10.1177/19386400231170967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Tendinopathy of the foot and ankle is a common clinical problem for which the exact etiology is poorly understood. The field of epigenetics has been a recent focus of this investigation. The purpose of this article was to review the genomic advances in foot and ankle tendinopathy that could potentially be used to stratify disease risk and create preventative or therapeutic agents. A multi-database search of PubMed, Cochrane, Google Scholar, and clinicaltrials.gov from January 1, 2000 to July 1, 2022 was performed. A total of 18 articles met inclusion and exclusion criteria for this review. The majority of such research utilized case-control candidate gene association to identify different genetic risk factors associated with chronic tendinopathy. Polymorphisms in collagen genes COL5A1, COL27A1, and COL1A1 were noted at a significantly higher frequency in Achilles tendinopathy versus control groups. Other allelic variations that were observed at an increased incidence in Achilles tendinopathy were TNC and CASP8. The extracellular matrix (ECM) demonstrated macroscopic changes in Achilles tendinopathy, including an increase in aggrecan and biglycan mRNA expression, and increased expression of multiple matrix metalloproteinases. Cytokine expression was also influenced in pathology and aberrantly demonstrated dynamic response to mechanical load. The pathologic accumulation of ECM proteins and cytokine expression alters the adaptive response normal tendon has to physiologic stress, further propagating the risk for tendinopathy. By identifying and understanding the epigenetic mediators that lead to tendinopathy, therapeutic agents can be developed to target the exact underlying etiology and minimize side effects.Level of Evidence: Level IV: Systematic Review of Level II-IV Studies.
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Affiliation(s)
- Samantha Williams
- Department of Podiatric Surgery, Silicon Valley Reconstructive Foot and Ankle Fellowship, Palo Alto Medical Foundation, Mountain View, California
| | - Chandler Ligas
- Department of Podiatric Surgery, Silicon Valley Reconstructive Foot and Ankle Fellowship, Palo Alto Medical Foundation, Mountain View, California
| | - Lawrence Oloff
- Department of Podiatric Surgery, Silicon Valley Reconstructive Foot and Ankle Fellowship, Palo Alto Medical Foundation, Mountain View, California
- St. Mary's Medical Center, San Francisco, California
| | - Teri E Klein
- Departments of Biomedical Data Science and Medicine, Stanford Center for Biomedical Informatics Research (BMIR), and Stanford University, Stanford, California
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Lu J, Li H, Zhang Z, Xu R, Wang J, Jin H. Platelet-rich plasma in the pathologic processes of tendinopathy: a review of basic science studies. Front Bioeng Biotechnol 2023; 11:1187974. [PMID: 37545895 PMCID: PMC10401606 DOI: 10.3389/fbioe.2023.1187974] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 07/10/2023] [Indexed: 08/08/2023] Open
Abstract
Tendinopathy is a medical condition that includes a spectrum of inflammatory and degenerative tendon changes caused by traumatic or overuse injuries. The pathological mechanism of tendinopathy has not been well defined, and no ideal treatment is currently available. Platelet-rich plasma (PRP) is an autologous whole blood derivative containing a variety of cytokines and other protein components. Various basic studies have found that PRP has the therapeutic potential to promote cell proliferation and differentiation, regulate angiogenesis, increase extracellular matrix synthesis, and modulate inflammation in degenerative tendons. Therefore, PRP has been widely used as a promising therapeutic agent for tendinopathy. However, controversies exist over the optimal treatment regimen and efficacy of PRP for tendinopathy. This review focuses on the specific molecular and cellular mechanisms by which PRP manipulates tendon healing to better understand how PRP affects tendinopathy and explore the reason for the differences in clinical trial outcomes. This article has also pointed out the future direction of basic research and clinical application of PRP in the treatment of tendinopathy, which will play a guiding role in the design of PRP treatment protocols for tendinopathy.
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Affiliation(s)
- Jialin Lu
- Department of Pain, The Second Hospital of Jilin University, Changchun, China
- Norman Bethune Health Science Center of Jilin University, Changchun, China
| | - Han Li
- Norman Bethune Health Science Center of Jilin University, Changchun, China
| | - Ziyu Zhang
- Norman Bethune Health Science Center of Jilin University, Changchun, China
| | - Rui Xu
- Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jincheng Wang
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Hui Jin
- Department of Pain, The Second Hospital of Jilin University, Changchun, China
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
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Cramer A, Højfeldt G, Schjerling P, Agergaard J, van Hall G, Olsen J, Hölmich P, Kjaer M, Barfod KW. Achilles Tendon Tissue Turnover Before and Immediately After an Acute Rupture. Am J Sports Med 2023; 51:2396-2403. [PMID: 37313851 DOI: 10.1177/03635465231177890] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
BACKGROUND An Achilles tendon rupture (ATR) is a frequent injury and results in the activation of tendon cells and collagen expression, but it is unknown to what extent turnover of the tendon matrix is altered before or after a rupture. PURPOSE/HYPOTHESIS The purpose of this study was to characterize tendon tissue turnover before and immediately after an acute rupture in patients. It was hypothesized that a rupture would result in pronounced collagen synthesis in the early phase (first 2 weeks) after the injury. STUDY DESIGN Cross-sectional study; Level of evidence, 3. METHODS The study included patients (N = 18) eligible for surgery after an ATR. At the time of inclusion, the patients ingested deuterium oxide (2H2O) orally, and on the day of surgery (within 14 days of the injury), they received a 3-hour flood-primed infusion of an 15N-proline tracer. During surgery, the patients had 1 biopsy specimen taken from the ruptured part of the Achilles tendon and 1 that was 3 to 5 cm proximal to the rupture as a control. The biopsy specimens were analyzed for carbon-14 (14C) levels in the tissue to calculate long-term turnover (years), incorporation of 2H-alanine (from 2H2O) into the tissue to calculate the fractional synthesis rate (FSR) of proteins in the short term (days), and incorporation of 15N-proline into the tissue to calculate the acute FSR (hours). RESULTS Both the rupture and the control samples showed consistently lower levels of 14C compared with the predicted level of 14C in a healthy tendon, which indicated increased tendon turnover in a fraction (48% newly synthesized) of the Achilles tendon already for a prolonged period before the rupture. Over the first days after the rupture, the synthesis rate for collagen was relatively constant, and the average synthesis rate on the day of surgery (2-14 days after the rupture) was 0.025% per hour, irrespective of the length of time after a rupture and the site of sampling (rupture vs control). No differences were found in the FSR between the rupture and control samples in the days after the rupture. CONCLUSION Higher than normal tissue turnover in the Achilles tendon before a rupture indicated that changes in the tendon tissue preceded the injury. In addition, we observed no increase in tendon collagen tissue turnover in the first 2 weeks after an ATR. This favors the view that an increase in the formation of new tendon collagen is not an immediate phenomenon during the regeneration of ruptured tendons in patients. REGISTRATION NCT03931486 (ClinicalTrials.gov identifier).
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Affiliation(s)
- Allan Cramer
- Sports Orthopedic Research Center-Copenhagen, Department of Orthopedic Surgery, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Grith Højfeldt
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Peter Schjerling
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jakob Agergaard
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Gerrit van Hall
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Metabolomics Core Facility, Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jesper Olsen
- Aarhus AMS Centre, Department of Physics and Astronomy, Aarhus University, Aarhus, Denmark
| | - Per Hölmich
- Sports Orthopedic Research Center-Copenhagen, Department of Orthopedic Surgery, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Michael Kjaer
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kristoffer Weisskirchner Barfod
- Sports Orthopedic Research Center-Copenhagen, Department of Orthopedic Surgery, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
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11
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Li H, Korcari A, Ciufo D, Mendias CL, Rodeo SA, Buckley MR, Loiselle AE, Pitt GS, Cao C. Increased Ca 2+ signaling through Ca V 1.2 induces tendon hypertrophy with increased collagen fibrillogenesis and biomechanical properties. FASEB J 2023; 37:e23007. [PMID: 37261735 PMCID: PMC10254118 DOI: 10.1096/fj.202300607r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/03/2023] [Accepted: 05/17/2023] [Indexed: 06/02/2023]
Abstract
Tendons are tension-bearing tissues transmitting force from muscle to bone for body movement. This mechanical loading is essential for tendon development, homeostasis, and healing after injury. While Ca2+ signaling has been studied extensively for its roles in mechanotransduction, regulating muscle, bone, and cartilage development and homeostasis, knowledge about Ca2+ signaling and the source of Ca2+ signals in tendon fibroblast biology are largely unknown. Here, we investigated the function of Ca2+ signaling through CaV 1.2 voltage-gated Ca2+ channel in tendon formation. Using a reporter mouse, we found that CaV 1.2 is highly expressed in tendon during development and downregulated in adult homeostasis. To assess its function, we generated ScxCre;CaV 1.2TS mice that express a gain-of-function mutant CaV 1.2 in tendon. We found that mutant tendons were hypertrophic, with more tendon fibroblasts but decreased cell density. TEM analyses demonstrated increased collagen fibrillogenesis in the hypertrophic tendons. Biomechanical testing revealed that the hypertrophic tendons display higher peak load and stiffness, with no changes in peak stress and elastic modulus. Proteomic analysis showed no significant difference in the abundance of type I and III collagens, but mutant tendons had about two-fold increase in other ECM proteins such as tenascin C, tenomodulin, periostin, type XIV and type VIII collagens, around 11-fold increase in the growth factor myostatin, and significant elevation of matrix remodeling proteins including Mmp14, Mmp2, and cathepsin K. Taken together, these data highlight roles for increased Ca2+ signaling through CaV 1.2 on regulating expression of myostatin growth factor and ECM proteins for tendon collagen fibrillogenesis during tendon formation.
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Affiliation(s)
- Haiyin Li
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopeadics, University of Rochester Medical Center, Rochester, NY, USA
| | - Antonion Korcari
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Engineering, University of Rochester Medical Center, Rochester, NY, USA
| | - David Ciufo
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopeadics, University of Rochester Medical Center, Rochester, NY, USA
| | | | - Scott A. Rodeo
- Sports Medicine and Shoulder Service, Hospital for Special Surgery, New York, NY, USA
| | - Mark R. Buckley
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Engineering, University of Rochester Medical Center, Rochester, NY, USA
| | - Alayna E. Loiselle
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopeadics, University of Rochester Medical Center, Rochester, NY, USA
| | - Geoffrey S. Pitt
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Chike Cao
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopeadics, University of Rochester Medical Center, Rochester, NY, USA
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12
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Nguyen PK, Hart C, Hall K, Holt I, Kuo CK. Establishing in vivo and ex vivo chick embryo models to investigate fetal tendon healing. Sci Rep 2023; 13:9600. [PMID: 37311784 PMCID: PMC10264358 DOI: 10.1038/s41598-023-35408-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 05/17/2023] [Indexed: 06/15/2023] Open
Abstract
Injured adult tendons heal fibrotically and possess high re-injury rates, whereas fetal tendons appear to heal scarlessly. However, knowledge of fetal tendon wound healing is limited due in part to the need for an accessible animal model. Here, we developed and characterized an in vivo and ex vivo chick embryo tendon model to study fetal tendon healing. In both models, injury sites filled rapidly with cells and extracellular matrix during healing, with wound closure occurring faster in vivo. Tendons injured at an earlier embryonic stage improved mechanical properties to levels similar to non-injured controls, whereas tendons injured at a later embryonic stage did not. Expression levels of tendon phenotype markers, collagens, collagen crosslinking regulators, matrix metalloproteinases, and pro-inflammatory mediators exhibited embryonic stage-dependent trends during healing. Apoptosis occurred during healing, but ex vivo tendons exhibited higher levels of apoptosis than tendons in vivo. Future studies will use these in vivo and ex vivo chick embryo tendon injury models to elucidate mechanisms of stage-specific fetal tendon healing to inform the development of therapeutic approaches to regeneratively heal adult tendons.
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Affiliation(s)
- Phong K Nguyen
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Fischell Department of Bioengineering, University of Maryland, 4108 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Christoph Hart
- Fischell Department of Bioengineering, University of Maryland, 4108 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Kaitlyn Hall
- Fischell Department of Bioengineering, University of Maryland, 4108 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Iverson Holt
- Fischell Department of Bioengineering, University of Maryland, 4108 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - Catherine K Kuo
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
- Fischell Department of Bioengineering, University of Maryland, 4108 A. James Clark Hall, 8278 Paint Branch Drive, College Park, MD, 20742, USA.
- Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA.
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13
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Sheng H, Zhang J, Pan C, Wang S, Gu S, Li F, Ma Y, Ma Y. Genome-wide identification of bovine ADAMTS gene family and analysis of its expression profile in the inflammatory process of mammary epithelial cells. Int J Biol Macromol 2023:125304. [PMID: 37315674 DOI: 10.1016/j.ijbiomac.2023.125304] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/29/2023] [Accepted: 06/04/2023] [Indexed: 06/16/2023]
Abstract
ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS) are secreted, multi-domain matrix-related zinc endopeptidases that play a role in organogenesis, assembly and degradation of extracellular matrix (ECM), cancer and inflammation. Genome-wide identification and analysis of the bovine ADAMTS gene family has not yet been carried out. In this study, 19 ADAMTS family genes were identified in Bos taurus by genome-wide bioinformatics analysis, and they were unevenly distributed on 12 chromosomes. Phylogenetic analysis shows that the Bos taurus ADAMTS are divided into eight subfamilies, with highly consistent gene structures and motifs within the same subfamily. Collinearity analysis showed that the Bos taurus ADAMTS gene family is homologous to other bovine subfamily species, and many ADAMTS genes may be derived from tandem replication and segmental replication. In addition, based on the analysis of RNA-seq data, we found the expression pattern of ADAMTS gene in different tissues. Meanwhile, we also analyzed the expression profile of ADAMTS gene in the inflammatory response of bovine mammary epithelial cells (BMECs) stimulated by LPS by qRT-PCR. The results can provide ideas for understanding the evolutionary relationship and expression pattern of ADAMTS gene in Bovidae, and clarify the theoretical basis of the function of ADAMTS in inflammation.
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Affiliation(s)
- Hui Sheng
- School of Agriculture, Ningxia University, Yinchuan 750021, China; Key Laboratory of Ruminant Molecular and Cellular Breeding, School of Agriculture, Ningxia University, Yinchuan 750021, China
| | - Junxing Zhang
- School of Agriculture, Ningxia University, Yinchuan 750021, China; Key Laboratory of Ruminant Molecular and Cellular Breeding, School of Agriculture, Ningxia University, Yinchuan 750021, China
| | - Cuili Pan
- School of Agriculture, Ningxia University, Yinchuan 750021, China; Key Laboratory of Ruminant Molecular and Cellular Breeding, School of Agriculture, Ningxia University, Yinchuan 750021, China
| | - Shuzhe Wang
- School of Agriculture, Ningxia University, Yinchuan 750021, China; Key Laboratory of Ruminant Molecular and Cellular Breeding, School of Agriculture, Ningxia University, Yinchuan 750021, China
| | - Shuaifeng Gu
- School of Agriculture, Ningxia University, Yinchuan 750021, China; Key Laboratory of Ruminant Molecular and Cellular Breeding, School of Agriculture, Ningxia University, Yinchuan 750021, China
| | - Fen Li
- School of Agriculture, Ningxia University, Yinchuan 750021, China; Key Laboratory of Ruminant Molecular and Cellular Breeding, School of Agriculture, Ningxia University, Yinchuan 750021, China
| | - Yanfen Ma
- School of Agriculture, Ningxia University, Yinchuan 750021, China; Key Laboratory of Ruminant Molecular and Cellular Breeding, School of Agriculture, Ningxia University, Yinchuan 750021, China
| | - Yun Ma
- School of Agriculture, Ningxia University, Yinchuan 750021, China; Key Laboratory of Ruminant Molecular and Cellular Breeding, School of Agriculture, Ningxia University, Yinchuan 750021, China.
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14
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Fitzgerald MJ, Mustapich T, Liang H, Larsen CG, Nellans KW, Grande DA. Tendon Transection Healing Can Be Improved With Adipose-Derived Stem Cells Cultured With Growth Differentiation Factor 5 and Platelet-Derived Growth Factor. Hand (N Y) 2023; 18:436-445. [PMID: 34340572 PMCID: PMC10152530 DOI: 10.1177/15589447211028929] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND As hand surgeons, tendon injuries and lacerations are a particularly difficult problem to treat, as poor healing potential and adhesions hamper optimal recovery. Adipose-derived stem cells (ADSCs) have been shown to aid in rat Achilles tendon healing after a puncture defect, and this model can be used to study tendon healing in the upper extremity. We hypothesized that ADSCs cultured with growth differentiation factor 5 (GDF5) and platelet-derived growth factor (PDGF) would improve tendon healing after a transection injury. METHODS Rat Achilles tendons were transected and then left either unrepaired or repaired. Both groups were treated with a hydrogel alone, a hydrogel with ADSCs, or a hydrogel with ADSCs that were cultured with GDF5 and PDGF prior to implantation. Tissue harvested from the tendons was evaluated for gene expression of several genes known to play an important role in successful tendon healing. Histological examination of the tendon healing was also performed. RESULTS In both repaired and unrepaired tendons, those treated with ADSCs cultured with GDF5/PDGF prior to implantation showed the best tendon fiber organization, the smallest gaps, and the most organized blood vessels. Treatment with GDF5/PDGF increased expression of the protenogenesis gene SOX9, promoted cell-to-cell connections, improved cellular proliferation, and enhanced tissue remodeling. CONCLUSIONS Adipose-derived stem cells cultured with GDF5/PDGF prior to implantation can promote tendon repair by improving cellular proliferation, tenogenesis, and vascular infiltration. This effect results in a greater degree of organized tendon healing.
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Affiliation(s)
| | | | | | | | - Kate W. Nellans
- Northwell Health, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Daniel A. Grande
- Northwell Health, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
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15
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Chhana A, Pool B, Callon KE, Naot D, Gao R, Coleman B, Cornish J, McCarthy GM, Dalbeth N. Basic calcium phosphate crystals induce the expression of extracellular matrix remodelling enzymes in tenocytes. Rheumatology (Oxford) 2023; 62:1343-1349. [PMID: 35809060 DOI: 10.1093/rheumatology/keac392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 07/02/2022] [Accepted: 07/02/2022] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES Basic calcium phosphate (BCP) crystals contribute to several syndromes associated with tendon disease, including acute calcific tendinitis and Milwaukee shoulder syndrome. Interactions between BCP crystals and tenocytes (tendon cells) may contribute to these clinical syndromes. This study aimed to determine the direct effects of BCP crystals on tenocyte function and viability. METHODS In vitro assays were used to assess changes in human tenocytes cultured with BCP crystals. Real-time PCR was used to determine changes in the expression of tendon-related genes and extracellular matrix remodelling enzymes (MMPs; a disintegrin and metalloproteases, ADAMTS; and tissue inhibitor of metalloproteinases, TIMPs). ELISA was used to measure protein concentrations in tenocyte supernatants. MTT and alamarBlue™ assays were used to determine changes in cell viability. RESULTS BCP crystals upregulated tenocyte gene expression of MMP-1, MMP-3, ADAMTS-4 and TIMP-1 after 24 h. Time-course experiments showed expression peaked at 8 h for TIMP-1 and 48 h for MMP-1 and ADAMTS-4. Cyclooxygenase (COX)-1 gene expression was upregulated after 48 h. Tenocytes did not alter expression of scleraxis and tendon collagens, and expression of pro-inflammatory cytokines was not induced with BCP crystals. BCP crystals increased tenocyte release of prostaglandin E2 (PGE2) and MMP-1 protein after 24 h. However, neither COX-1 inhibition nor COX-2 inhibition led to consistent change in BCP crystal-induced tenocyte gene expression of extracellular matrix remodelling enzymes. BCP crystals had no effect on tenocyte viability. CONCLUSION BCP crystals induce extracellular matrix remodelling enzymes, but not inflammatory cytokines, in tenocytes.
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Affiliation(s)
- Ashika Chhana
- Bone & Joint Research Group, Department of Medicine, University of Auckland
| | - Bregina Pool
- Bone & Joint Research Group, Department of Medicine, University of Auckland
| | - Karen E Callon
- Bone & Joint Research Group, Department of Medicine, University of Auckland
| | - Dorit Naot
- Bone & Joint Research Group, Department of Medicine, University of Auckland
| | - Ryan Gao
- Bone & Joint Research Group, Department of Medicine, University of Auckland
| | - Brendan Coleman
- Department of Orthopaedic Surgery, Middlemore Hospital, Auckland, New Zealand
| | - Jillian Cornish
- Bone & Joint Research Group, Department of Medicine, University of Auckland
| | - Geraldine M McCarthy
- Department of Rheumatology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Nicola Dalbeth
- Bone & Joint Research Group, Department of Medicine, University of Auckland
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16
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Abadin AA, Orr JP, Lloyd AR, Henning PT, Pourcho A. An Evidence-Based Approach to Orthobiologics for Tendon Disorders. Phys Med Rehabil Clin N Am 2023; 34:83-103. [PMID: 36410893 DOI: 10.1016/j.pmr.2022.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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17
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Li H, Korcari A, Ciufo D, Mendias CL, Rodeo SA, Buckley MR, Loiselle AE, Pitt GS, Cao C. Increased Ca 2+ signaling through Ca V 1.2 induces tendon hypertrophy with increased collagen fibrillogenesis and biomechanical properties. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.24.525119. [PMID: 36747837 PMCID: PMC9900778 DOI: 10.1101/2023.01.24.525119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Tendons are tension-bearing tissues transmitting force from muscle to bone for body movement. This mechanical loading is essential for tendon development, homeostasis, and healing after injury. While Ca 2+ signaling has been studied extensively for its roles in mechanotransduction, regulating muscle, bone and cartilage development and homeostasis, knowledge about Ca 2+ signaling and the source of Ca 2+ signals in tendon fibroblast biology are largely unknown. Here, we investigated the function of Ca 2+ signaling through Ca V 1.2 voltage-gated Ca 2+ channel in tendon formation. Using a reporter mouse, we found that Ca V 1.2 is highly expressed in tendon during development and downregulated in adult homeostasis. To assess its function, we generated ScxCre;Ca V 1.2 TS mice that express a gain-of-function mutant Ca V 1.2 channel (Ca V 1.2 TS ) in tendon. We found that tendons in the mutant mice were approximately 2/3 larger and had more tendon fibroblasts, but the cell density of the mutant mice decreased by around 22%. TEM analyses demonstrated increased collagen fibrillogenesis in the hypertrophic tendon. Biomechanical testing revealed that the hypertrophic Achilles tendons display higher peak load and stiffness, with no changes in peak stress and elastic modulus. Proteomics analysis reveals no significant difference in the abundance of major extracellular matrix (ECM) type I and III collagens, but mutant mice had about 2-fold increase in other ECM proteins such as tenascin C, tenomodulin, periostin, type XIV and type VIII collagens, around 11-fold increase in the growth factor of TGF-β family myostatin, and significant elevation of matrix remodeling proteins including Mmp14, Mmp2 and cathepsin K. Taken together, these data highlight roles for increased Ca 2+ signaling through Ca V 1.2 on regulating expression of myostatin growth factor and ECM proteins for tendon collagen fibrillogenesis during tendon formation.
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18
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Smith EJ, Beaumont RE, McClellan A, Sze C, Palomino Lago E, Hazelgrove L, Dudhia J, Smith RKW, Guest DJ. Tumour necrosis factor alpha, interleukin 1 beta and interferon gamma have detrimental effects on equine tenocytes that cannot be rescued by IL-1RA or mesenchymal stromal cell-derived factors. Cell Tissue Res 2023; 391:523-544. [PMID: 36543895 PMCID: PMC9974687 DOI: 10.1007/s00441-022-03726-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 12/10/2022] [Indexed: 12/24/2022]
Abstract
Tendon injuries occur commonly in both human and equine athletes, and poor tendon regeneration leads to functionally deficient scar tissue and an increased frequency of re-injury. Despite evidence suggesting inadequate resolution of inflammation leads to fibrotic healing, our understanding of the inflammatory pathways implicated in tendinopathy remains poorly understood, meaning successful targeted treatments are lacking. Here, we demonstrate IL-1β, TNFα and IFN-γ work synergistically to induce greater detrimental consequences for equine tenocytes than when used individually. This includes altering tendon associated and matrix metalloproteinase gene expression and impairing the cells' ability to contract a 3-D collagen gel, a culture technique which more closely resembles the in vivo environment. Moreover, these adverse effects cannot be rescued by direct suppression of IL-1β using IL-1RA or factors produced by BM-MSCs. Furthermore, we provide evidence that NF-κB, but not JNK, P38 MAPK or STAT 1, is translocated to the nucleus and able to bind to DNA in tenocytes following TNFα and IL-1β stimulation, suggesting this signalling cascade may be responsible for the adverse downstream consequences of these inflammatory cytokines. We suggest a superior approach for treatment of tendinopathy may therefore be to target specific signalling pathways such as NF-κB.
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Affiliation(s)
- Emily J Smith
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK.
| | - Ross E Beaumont
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK
| | - Alyce McClellan
- Centre for Preventative Medicine, Animal Health Trust, Newmarket, Suffolk, CB8 7UU, UK
| | - Cheryl Sze
- Centre for Preventative Medicine, Animal Health Trust, Newmarket, Suffolk, CB8 7UU, UK
| | - Esther Palomino Lago
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK
| | - Liberty Hazelgrove
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK
- Kingston University, River House, 53-57 High Street, Kingston upon Thames, Surrey, KT1 1LQ, UK
| | - Jayesh Dudhia
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK
| | - Roger K W Smith
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK
| | - Deborah J Guest
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK.
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19
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James S, Daffy J, Cook J, Samiric T. Short-Term Exposure to Ciprofloxacin Reduces Proteoglycan Loss in Tendon Explants. Genes (Basel) 2022; 13:genes13122210. [PMID: 36553476 PMCID: PMC9777606 DOI: 10.3390/genes13122210] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/22/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
Fluoroquinolone antibiotics are associated with increased risk of tendinopathy and tendon rupture, which can occur well after cessation of treatment. We have previously reported that the fluoroquinolone ciprofloxacin (CPX) reduced proteoglycan synthesis in equine tendon explants. This study aimed to determine the effects of CPX on proteoglycan catabolism and whether any observed effects are reversible. Equine superficial digital flexor tendon explant cultures were treated for 4 days with 1, 10, 100 or 300 µg/mL CPX followed by 8 days without CPX. The loss of [35S]-labelled proteoglycans and chemical pool of aggrecan and versican was studied as well as the gene expression levels of matrix-degrading enzymes responsible for proteoglycan catabolism. CPX suppressed [35S]-labelled proteoglycan and total aggrecan loss from the explants, although not in a dose-dependent manner, which coincided with downregulation of mRNA expression of MMP-9, -13, ADAMTS-4, -5. The suppressed loss of proteoglycans was reversed upon removal of the fluoroquinolone with concurrent recovery of MMP and ADAMTS mRNA expression, and downregulated TIMP-2 and upregulated TIMP-1 expression. No changes in MMP-3 expression by CPX was observed at any stage. These findings suggest that CPX suppresses proteoglycan catabolism in tendon, and this is partially attributable to downregulation of matrix-degrading enzymes.
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Affiliation(s)
- Stuart James
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Melbourne, VIC 3086, Australia
| | - John Daffy
- Department of Infectious Diseases, St Vincent’s Hospital, Melbourne, VIC 3065, Australia
| | - Jill Cook
- Sports and Exercise Medicine Research Centre, La Trobe University, Melbourne, VIC 3086, Australia
| | - Tom Samiric
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Melbourne, VIC 3086, Australia
- Correspondence:
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20
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Epigenetic Alterations in Sports-Related Injuries. Genes (Basel) 2022; 13:genes13081471. [PMID: 36011382 PMCID: PMC9408207 DOI: 10.3390/genes13081471] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/11/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
It is a well-known fact that physical activity benefits people of all age groups. However, highly intensive training, maladaptation, improper equipment, and lack of sufficient rest lead to contusions and sports-related injuries. From the perspectives of sports professionals and those performing regular–amateur sports activities, it is important to maintain proper levels of training, without encountering frequent injuries. The bodily responses to physical stress and intensive physical activity are detected on many levels. Epigenetic modifications, including DNA methylation, histone protein methylation, acetylation, and miRNA expression occur in response to environmental changes and play fundamental roles in the regulation of cellular activities. In the current review, we summarise the available knowledge on epigenetic alterations present in tissues and organs (e.g., muscles, the brain, tendons, and bones) as a consequence of sports-related injuries. Epigenetic mechanism observations have the potential to become useful tools in sports medicine, as predictors of approaching pathophysiological alterations and injury biomarkers that have already taken place.
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21
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Chen YC, Chang HN, Pang JHS, Lin LP, Chen JM, Yu TY, Tsai WC. Lidocaine Inhibited Tendon Cell Proliferation and Extracellular Matrix Production by Down Regulation of Cyclin A, CDK2, Type I and Type III Collagen Expression. Int J Mol Sci 2022; 23:ijms23158787. [PMID: 35955918 PMCID: PMC9368801 DOI: 10.3390/ijms23158787] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 07/28/2022] [Accepted: 08/03/2022] [Indexed: 11/30/2022] Open
Abstract
Lidocaine injection is a common treatment for tendon injuries. However, the evidence suggests that lidocaine is toxic to tendon cells. This study investigated the effects of lidocaine on cultured tendon cells, focusing on the molecular mechanisms underlying cell proliferation and extracellular matrix (ECM) production. Tendon cells cultured from rat Achilles tendons were treated with 0.5, 1.0, or 1.5 mg/mL lidocaine for 24 h. Cell proliferation was evaluated by Cell Counting Kit 8 (CCK-8) assay and bromodeoxyuridine (BrdU) assay. Cell apoptosis was assessed by Annexin V and propidium iodide (PI) stain. Cell cycle progression and cell mitosis were assessed through flow cytometry and immunofluorescence staining, respectively. The expression of cyclin E, cyclin A, cyclin-dependent kinase 2 (CDK2), p21, p27, p53, matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9), type I collagen, and type III collagen were examined through Western blotting, and the enzymatic activity of MMP-9 was determined through gelatin zymography. Lidocaine reduced cell proliferation and reduced G1/S transition and cell mitosis. Lidocaine did not have a significant negative effect on cell apoptosis. Lidocaine significantly inhibited cyclin A and CDK2 expression but promoted p21, p27, and p53 expression. Furthermore, the expression of MMP-2 and MMP-9 increased, whereas that of type I and type III collagen decreased. Lidocaine also increased the enzymatic activity of MMP-9. Our findings support the premise that lidocaine inhibits tendon cell proliferation by changing the expression of cell-cycle-related proteins and reduces ECM production by altering levels of MMPs and collagens.
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Affiliation(s)
- Yen-Chia Chen
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan City 33302, Taiwan
| | - Hsiang-Ning Chang
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan City 33302, Taiwan
| | - Jong-Hwei Su Pang
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan City 33302, Taiwan
- Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan City 33302, Taiwan
| | - Li-Ping Lin
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan City 33302, Taiwan
- Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan City 33302, Taiwan
| | - Jing-Min Chen
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan City 33302, Taiwan
| | - Tung-Yang Yu
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan City 33302, Taiwan
| | - Wen-Chung Tsai
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan City 33302, Taiwan
- School of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan
- Center of Comprehensive Sports Medicine, Chang Gung Memorial Hospital, Taoyuan City 33302, Taiwan
- Correspondence:
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22
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Lu J, Jiang L, Chen Y, Lyu K, Zhu B, Li Y, Liu X, Liu X, Long L, Wang X, Xu H, Wang D, Li S. The Functions and Mechanisms of Basic Fibroblast Growth Factor in Tendon Repair. Front Physiol 2022; 13:852795. [PMID: 35770188 PMCID: PMC9234302 DOI: 10.3389/fphys.2022.852795] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 05/20/2022] [Indexed: 11/17/2022] Open
Abstract
Tendon injury is a disorder of the musculoskeletal system caused by overuse or trauma, which is characterized by pain and limitations in joint function. Since tendon healing is slowly and various treatments are generally ineffective, it remains a clinically challenging problem. Recent evidences suggest that basic fibroblast growth factor (bFGF) not only plays an important role in tendon healing, but also shows a positive effect in laboratory experimentations. The purpose of this review is to summarize the effects of bFGF in the tendon healing. Firstly, during the inflammatory phase, bFGF stimulates the proliferation and differentiation of vascular endothelial cells to foster neovascularization. Furthermore, bFGF enhances the production of pro-inflammatory factors during the early phase of tendon healing, thereby accelerating the inflammatory response. Secondly, the cell proliferation phase is accompanied by the synthesis of a large number of extracellular matrix components. bFGF speeds up tendon healing by stimulating fibroblasts to secrete type III collagen. Lastly, the remodeling phase is characterized by the transition from type III collagen to type I collagen, which can be promoted by bFGF. However, excessive injection of bFGF can cause tendon adhesions as well as scar tissue formation. In future studies, we need to explore further applications of bFGF in the tendon healing process.
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Affiliation(s)
- Jingwei Lu
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Li Jiang
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Yixuan Chen
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Kexin Lyu
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Bin Zhu
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Yujie Li
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Xueli Liu
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Xinyue Liu
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Longhai Long
- The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Xiaoqiang Wang
- The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Houping Xu
- The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
- *Correspondence: Houping Xu, ; Dingxuan Wang, ; Sen Li,
| | - Dingxuan Wang
- School of Physical Education, Southwest Medical University, Luzhou, China
- *Correspondence: Houping Xu, ; Dingxuan Wang, ; Sen Li,
| | - Sen Li
- The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
- *Correspondence: Houping Xu, ; Dingxuan Wang, ; Sen Li,
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Electrospun, Resorbable, Drug-Eluting, Nanofibrous Membranes Promote Healing of Allograft Tendons. MEMBRANES 2022; 12:membranes12050529. [PMID: 35629855 PMCID: PMC9147671 DOI: 10.3390/membranes12050529] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 12/10/2022]
Abstract
In spite of advances in medical technology, the repair of Achilles tendon ruptures remains challenging. Reconstruction with an autograft tendon provides the advantage of a higher healing rate; nevertheless, the development of donor-site morbidity cannot be ignored. We developed biodegradable, drug-eluting, nanofibrous membranes employing an electrospinning technique and evaluated their effectiveness on the healing of allograft tendons. Poly-D-L-lactide-glycolide was used as the polymeric material for the nanofibers, while doxycycline was selected as the drug for delivery. The in vitro and in vivo drug-release profiles were investigated. The biomechanical properties of allografted Achilles tendons repaired using the nanofibrous membranes were tested in euthanized rabbits at 2-, 4-, and 6-week time intervals. Histological examination was performed for the evaluation of tissue reaction and tendon healing. The level of postoperative animal activity was also monitored using an animal behavior cage. The experimental results showed that the degradable nanofibers used as a vehicle could provide sustained release of doxycycline for 42 days after surgery with very low systemic drug concentration. Allograft Achilles tendon reconstruction assisted by drug-loaded nanofibers was associated with better biomechanical properties at 6 weeks post-surgery. In addition, the animals exhibited a better level of activity after surgery. The use of drug-eluting, nanofibrous membranes could enhance healing in Achilles tendon allograft reconstruction surgery.
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24
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Bolam SM, Konar S, Park YE, Callon KE, Workman J, Monk AP, Coleman B, Cornish J, Vickers MH, Munro JT, Musson DS. A high-fat diet has negative effects on tendon resident cells in an in vivo rat model. INTERNATIONAL ORTHOPAEDICS 2022; 46:1181-1190. [PMID: 35201374 PMCID: PMC9001221 DOI: 10.1007/s00264-022-05340-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 02/04/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Tendinopathy is a major complication of diet-induced obesity. However, the effects of a high-fat diet (HFD) on tendon have not been well characterised. We aimed to determine: [1] the impact of a HFD on tendon properties and gene expression; and [2] whether dietary transition to a control diet (CD) could restore normal tendon health. METHODS Sprague-Dawley rats were randomised into three groups from weaning and fed either a: CD, HFD or HFD for 12 weeks and then CD thereafter (HF-CD). Biomechanical, histological and structural evaluation of the Achilles tendon was performed at 17 and 27 weeks of age. Tail tenocytes were isolated with growth rate and collagen production determined. Tenocytes and activated THP-1 cells were exposed to conditioned media (CM) of visceral adipose tissue explants, and gene expression was analysed. RESULTS There were no differences in the biomechanical, histological or structural tendon properties between groups. However, tenocyte growth and collagen production were increased in the HFD group at 27 weeks. There was lower SOX-9 expression in the HFD and HF-CD groups at 17 weeks and higher expression of collagen-Iα1 and matrix metalloproteinase-13 in the HFD group at 27 weeks. THP-1 cells exposed to adipose tissue CM from animals fed a HFD or HF-CD had lower expression of Il-10 and higher expression of Il-1β. CONCLUSIONS In this rodent model, a HFD negatively altered tendon cell characteristics. Dietary intervention restored some gene expression changes; however, adipose tissue secretions from the HF-CD group promoted an increased inflammatory state in macrophages. These changes may predispose tendon to injury and adverse events later in life.
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Affiliation(s)
- Scott M Bolam
- Department of Medicine, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand
- Department of Orthopedic Surgery, Auckland City Hospital, 2 Park Road, Grafton, Auckland, New Zealand
| | - Subhajit Konar
- Department of Medicine, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand
| | - Young-Eun Park
- Department of Medicine, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand
| | - Karen E Callon
- Department of Medicine, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand
| | - Josh Workman
- Chemical and Materials Engineering, University of Auckland, 5 Grafton Rd, Auckland, New Zealand
| | - A Paul Monk
- Department of Orthopedic Surgery, Auckland City Hospital, 2 Park Road, Grafton, Auckland, New Zealand
- Auckland Bioengineering Institute, University of Auckland, 70 Symonds St, Grafton, Auckland, New Zealand
| | - Brendan Coleman
- Department of Orthopedic Surgery, Middlemore Hospital, 100 Hospital Road, Otahuhu, Auckland, New Zealand
| | - Jillian Cornish
- Department of Medicine, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand
| | - Mark H Vickers
- Liggins Institute, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand
| | - Jacob T Munro
- Department of Medicine, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand
- Department of Orthopedic Surgery, Auckland City Hospital, 2 Park Road, Grafton, Auckland, New Zealand
| | - David S Musson
- Department of Medicine, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand.
- Department of Nutrition & Dietetics, University of Auckland, 85 Park Road, Grafton, 1023, Auckland, New Zealand.
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25
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Brazier J, Antrobus MR, Herbert AJ, Callus PC, Stebbings GK, Day SH, Heffernan SM, Kilduff LP, Bennett MA, Erskine RM, Raleigh SM, Collins M, Pitsiladis YP, Williams AG. Gene Variants Previously Associated with Reduced Soft Tissue Injury Risk: Part 1 - Independent Associations with Elite Status in Rugby. Eur J Sport Sci 2022; 23:726-735. [PMID: 35293840 DOI: 10.1080/17461391.2022.2053752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
AbstractThere is growing evidence of genetic contributions to tendon and ligament pathologies. Given the high incidence and severity of tendon and ligament injuries in elite rugby, we studied whether 13 gene polymorphisms previously associated with tendon/ligament injury were associated with elite athlete status. Participants from the RugbyGene project were 663 elite Caucasian male rugby athletes (RA) (mean (standard deviation) height 1.85 (0.07) m, mass 101 (12) kg, age 29 (7) yr), including 558 rugby union athletes (RU) and 105 rugby league athletes. Non-athletes (NA) were 909 Caucasian men and women (56% female; height 1.70 (0.10) m, mass 72 (13) kg, age 41 (23) yr). Genotypes were determined using TaqMan probes and groups compared using Χ2 and odds ratio (OR). COLGALT1 rs8090 AA genotype was more frequent in RA (27%) than NA (23%; P = 0.006). COL3A1 rs1800255 A allele was more frequent in RA (26%) than NA (23%) due to a greater frequency of GA genotype (39% vs 33%). For MIR608 rs4919510, RA had 1.7 times the odds of carrying the CC genotype compared to NA. MMP3 rs591058 TT genotype was less common in RA (25.1%) than NA (31.2%; P < 0.04). For NID1 rs4660148, RA had 1.6 times the odds of carrying the TT genotype compared to NA. It appears that elite rugby athletes have an inherited advantage that contributes to their elite status, possibly via resistance to soft tissue injury. These data may, in future, assist personalized management of injury risk amongst athletes.
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Affiliation(s)
- Jon Brazier
- Manchester Metropolitan University Institute of Sport, Manchester, UK.,Department of Sport and Exercise Sciences, Musculoskeletal Science and Sports Medicine Research Centre, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK.,Department of Psychology, Sport and Geography, University of Hertfordshire, Hatfield AL10 9AB, UK
| | - Mark R Antrobus
- Manchester Metropolitan University Institute of Sport, Manchester, UK.,Department of Sport and Exercise Sciences, Musculoskeletal Science and Sports Medicine Research Centre, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK.,Sport and Exercise Science, University of Northampton, Northampton NN1 5PH, UK
| | - Adam J Herbert
- Department of Sport and Exercise, School of Health Sciences, Birmingham City University, Birmingham, B15 3TN, UK
| | - Peter C Callus
- Manchester Metropolitan University Institute of Sport, Manchester, UK.,Department of Sport and Exercise Sciences, Musculoskeletal Science and Sports Medicine Research Centre, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK
| | - Georgina K Stebbings
- Manchester Metropolitan University Institute of Sport, Manchester, UK.,Department of Sport and Exercise Sciences, Musculoskeletal Science and Sports Medicine Research Centre, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK
| | - Stephen H Day
- Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK
| | - Shane M Heffernan
- Applied Sports Science Technology and Medicine Research Centre (A-STEM), Faculty of Science and Engineering, Swansea University, Swansea SA1 8EN, UK
| | - Liam P Kilduff
- Applied Sports Science Technology and Medicine Research Centre (A-STEM), Faculty of Science and Engineering, Swansea University, Swansea SA1 8EN, UK
| | - Mark A Bennett
- Applied Sports Science Technology and Medicine Research Centre (A-STEM), Faculty of Science and Engineering, Swansea University, Swansea SA1 8EN, UK
| | - Robert M Erskine
- Research Institute for Sport & Exercise Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK.,Institute of Sport, Exercise and Health, University College London, London, WC1E 6BT, UK
| | - Stuart M Raleigh
- School of Health Sciences, Coventry University, Coventry, CV1 5FB, UK
| | - Malcolm Collins
- Division of Exercise Science and Sports Medicine, Department of Human Biology, University of Cape Town, Cape Town, 7700, South Africa
| | - Yannis P Pitsiladis
- FIMS Reference Collaborating Centre of Sports Medicine for Anti-Doping Research, University of Brighton, Brighton, BN2 0YJ, UK
| | - Alun G Williams
- Manchester Metropolitan University Institute of Sport, Manchester, UK.,Department of Sport and Exercise Sciences, Musculoskeletal Science and Sports Medicine Research Centre, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK.,Applied Sports Science Technology and Medicine Research Centre (A-STEM), Faculty of Science and Engineering, Swansea University, Swansea SA1 8EN, UK.,Institute of Sport, Exercise and Health, University College London, London, WC1E 6BT, UK
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26
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Mesenchymal Stromal Cells Adapt to Chronic Tendon Disease Environment with an Initial Reduction in Matrix Remodeling. Int J Mol Sci 2021; 22:ijms222312798. [PMID: 34884602 PMCID: PMC8657831 DOI: 10.3390/ijms222312798] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 01/11/2023] Open
Abstract
Tendon lesions are common sporting injuries in humans and horses alike. The healing process of acute tendon lesions frequently results in fibrosis and chronic disease. In horses, local mesenchymal stromal cell (MSC) injection is an accepted therapeutic strategy with positive influence on acute lesions. Concerning the use of MSCs in chronic tendon disease, data are scarce but suggest less therapeutic benefit. However, it has been shown that MSCs can have a positive effect on fibrotic tissue. Therefore, we aimed to elucidate the interplay of MSCs and healthy or chronically diseased tendon matrix. Equine MSCs were cultured either as cell aggregates or on scaffolds from healthy or diseased equine tendons. Higher expression of tendon-related matrix genes and tissue inhibitors of metalloproteinases (TIMPs) was found in aggregate cultures. However, the tenogenic transcription factor scleraxis was upregulated on healthy and diseased tendon scaffolds. Matrix metalloproteinase (MMPs) expression and activity were highest in healthy scaffold cultures but showed a strong transient decrease in diseased scaffold cultures. The release of glycosaminoglycan and collagen was also higher in scaffold cultures, even more so in those with tendon disease. This study points to an early suppression of MSC matrix remodeling activity by diseased tendon matrix, while tenogenic differentiation remained unaffected.
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27
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Roberts JH, Halper J. Growth Factor Roles in Soft Tissue Physiology and Pathophysiology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:139-159. [PMID: 34807418 DOI: 10.1007/978-3-030-80614-9_6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Repair and healing of injured and diseased tendons has been traditionally fraught with apprehension and difficulties, and often led to rather unsatisfactory results. The burgeoning research field of growth factors has opened new venues for treatment of tendon disorders and injuries, and possibly for treatment of disorders of the aorta and major arteries as well. Several chapters in this volume elucidate the role of transforming growth factor β (TGFß) in pathogenesis of several heritable disorders affecting soft tissues, such as aorta, cardiac valves, and tendons and ligaments. Several members of the bone morphogenetic group either have been approved by the FDA for treatment of non-healing fractures or have been undergoing intensive clinical and experimental testing for use of healing bone fractures and tendon injuries. Because fibroblast growth factors (FGFs) are involved in embryonic development of tendons and muscles among other tissues and organs, the hope is that applied research on FGF biological effects will lead to the development of some new treatment strategies providing that we can control angiogenicity of these growth factors. The problem, or rather question, regarding practical use of imsulin-like growth factor I (IGF-I) in tendon repair is whether IGF-I acts independently or under the guidance of growth hormone. FGF2 or platelet-derived growth factor (PDGF) alone or in combination with IGF-I stimulates regeneration of periodontal ligament: a matter of importance in Marfan patients with periodontitis. In contrast, vascular endothelial growth factor (VEGF) appears to have rather deleterious effects on experimental tendon healing, perhaps because of its angiogenic activity and stimulation of matrix metalloproteinases-proteases whose increased expression has been documented in a variety of ruptured tendons. Other modalities, such as local administration of platelet-rich plasma (PRP) and/or of mesenchymal stem cells have been explored extensively in tendon healing. Though treatment with PRP and mesenchymal stem cells has met with some success in horses (who experience a lot of tendon injuries and other tendon problems), the use of PRP and mesenchymal stem cells in people has been more problematic and requires more studies before PRP and mesenchymal stem cells can become reliable tools in management of soft tissue injuries and disorders.
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Affiliation(s)
- Jennifer H Roberts
- Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA, USA
| | - Jaroslava Halper
- Department of Pathology, College of Veterinary Medicine, and Department of Basic Sciences, AU/UGA Medical Partnership, The University of Georgia, Athens, GA, USA.
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28
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Bolam SM, Satokar VV, Konar S, Coleman B, Monk AP, Cornish J, Munro JT, Vickers MH, Albert BB, Musson DS. A Maternal High Fat Diet Leads to Sex-Specific Programming of Mechanical Properties in Supraspinatus Tendons of Adult Rat Offspring. Front Nutr 2021; 8:729427. [PMID: 34589513 PMCID: PMC8473632 DOI: 10.3389/fnut.2021.729427] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/16/2021] [Indexed: 12/16/2022] Open
Abstract
Background: Over half of women of reproductive age are now overweight or obese. The impact of maternal high-fat diet (HFD) is emerging as an important factor in the development and health of musculoskeletal tissues in offspring, however there is a paucity of evidence examining its effects on tendon. Alterations in the early life environment during critical periods of tendon growth therefore have the potential to influence tendon health that cross the lifespan. We hypothesised that a maternal HFD would alter biomechanical, morphological and gene expression profiles of adult offspring rotator cuff tendon. Materials and Methods: Female Sprague-Dawley rats were randomly assigned to either: control diet (CD; 10% kcal or 43 mg/g from fat) or HFD (45% kcal or 235 mg/g from fat) 14 days prior to mating and throughout pregnancy and lactation. Eight female and male offspring from each maternal diet group were weaned onto a standard chow diet and then culled at postnatal day 100 for tissue collection. Supraspinatus tendons were used for mechanical testing and histological assessment (cellularity, fibre organisation, nuclei shape) and tail tendons were collected for gene expression analysis. Results: A maternal HFD increased the elasticity (Young's Modulus) in the supraspinatus tendon of male offspring. Female offspring tendon biomechanical properties were not affected by maternal HFD. Gene expression of SCX and COL1A1 were reduced in male and female offspring of maternal HFD, respectively. Despite this, tendon histological organisation were similar between maternal diet groups in both sexes. Conclusion: An obesogenic diet during pregnancy increased tendon elasticity in male, but not female, offspring. This is the first study to demonstrate that maternal diet can modulate the biomechanical properties of offspring tendon. A maternal HFD may be an important factor in regulating adult offspring tendon homeostasis that may predispose offspring to developing tendinopathies and adverse tendon outcomes in later life.
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Affiliation(s)
- Scott M. Bolam
- Bone and Joint Laboratory, University of Auckland, Auckland, New Zealand
- Department of Orthopaedic Surgery, Auckland City Hospital, Auckland, New Zealand
| | - Vidit V. Satokar
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Subhajit Konar
- Bone and Joint Laboratory, University of Auckland, Auckland, New Zealand
| | - Brendan Coleman
- Department of Orthopaedic Surgery, Middlemore Hospital, Auckland, New Zealand
| | - Andrew Paul Monk
- Department of Orthopaedic Surgery, Auckland City Hospital, Auckland, New Zealand
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Jillian Cornish
- Bone and Joint Laboratory, University of Auckland, Auckland, New Zealand
| | - Jacob T. Munro
- Bone and Joint Laboratory, University of Auckland, Auckland, New Zealand
- Department of Orthopaedic Surgery, Auckland City Hospital, Auckland, New Zealand
| | - Mark H. Vickers
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | | | - David S. Musson
- Bone and Joint Laboratory, University of Auckland, Auckland, New Zealand
- Department of Nutrition, University of Auckland, Auckland, New Zealand
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29
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Griffin C, Daniels K, Hill C, Franklyn-Miller A, Morin JB. A criteria-based rehabilitation program for chronic mid-portion Achilles tendinopathy: study protocol for a randomised controlled trial. BMC Musculoskelet Disord 2021; 22:695. [PMID: 34391384 PMCID: PMC8364697 DOI: 10.1186/s12891-021-04553-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 07/07/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Achilles tendinopathy (AT) is a common overuse injury in running-related sports where patients experience pain and impaired function which can persist. A graded rehabilitation program has been successful in reducing pain and improving function to enable a return to sport. The aim of this study is to compare the effectiveness of a criteria-based rehabilitation program including strength and reactive strength targets, with a previously successful rehabilitation program on changes in pain and function using the Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire. Secondary aims will be to assess changes in calf strength, reactive strength, and lower limb running and forward hop biomechanics over the course of a 12-week rehabilitation program, and long-term follow-up investigations. METHODS Sixty eligible participants with chronic mid-portion AT who train in running-based sports will be included in this study. They will be randomly assigned to a group that will follow an evidence-based rehabilitation program of daily exercises with progression guided by symptoms or a group performing 3 high-intensity rehabilitation sessions per week with individualised load targets progressing to reactive strength exercises. Testing will take place at baseline, week 6 and 12. Plantar flexor peak torque will be measured using isokinetic dynamometry, reactive strength will be measured using a drop jump and lower limb biomechanical variables will be measured during a single leg forward hurdle hop test and treadmill running using 3D motion analysis. Follow-up interviews will take place at 6, 12 and 24 months after beginning the program which will assess patient participation in sport and possible re-injury. DISCUSSION This is the first study to propose an individualised criteria-based graded rehabilitation program in patients in with chronic mid-portion Achilles tendinopathy where progression is guided by strength and reactive strength outcome measures. This study will provide a comprehensive assessment of plantar flexor strength, reactive strength and lower limb biomechanical variables in running and forward hopping with the VISA-A questionnaire as the primary outcome measure and long term post-intervention follow-up assessments performed. TRIAL REGISTRATION ClinicalTrials.gov (ID: NCT04384874 ). Registered retrospectively on April 23rd 2020.
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Affiliation(s)
- Colin Griffin
- Université Côte d'Azur, LAMHESS, Nice, France.
- Sports Surgery Clinic, Santry Demesne, Dublin 9, Ireland.
| | - Katherine Daniels
- Sports Surgery Clinic, Santry Demesne, Dublin 9, Ireland
- University of Bristol, Queen's School of Engineering, University Walk, Bristol, BS81TR, UK
- Department of Sport and Exercise Sciences, Manchester Metropolitan University, Manchester, UK
| | - Caroline Hill
- Sports Surgery Clinic, Santry Demesne, Dublin 9, Ireland
| | - Andrew Franklyn-Miller
- Sports Surgery Clinic, Santry Demesne, Dublin 9, Ireland
- Centre for Health, Exercise and Sports Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Jean-Benoît Morin
- Université Côte d'Azur, LAMHESS, Nice, France
- Sports Performance Research Institute New Zealand (SPRINZ), Auckland University of Technology, Auckland, New Zealand
- Univ Lyon, UJM-Saint-Etienne, Inter-university Laboratory of Human Movement Biology, EA 7424, F-42023, Saint-Etienne, France
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30
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Gaesser AM, Underwood C, Linardi RL, Even KM, Reef VB, Shetye SS, Mauck RL, King WJ, Engiles JB, Ortved KF. Evaluation of Autologous Protein Solution Injection for Treatment of Superficial Digital Flexor Tendonitis in an Equine Model. Front Vet Sci 2021; 8:697551. [PMID: 34291103 PMCID: PMC8287003 DOI: 10.3389/fvets.2021.697551] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/01/2021] [Indexed: 11/21/2022] Open
Abstract
Autologous protein solution (APS) has been used anecdotally for intralesional treatment of tendon and ligament injuries, however, its use in these injuries has never been studied in vivo. Our objective was to evaluate the effect of APS on tendon healing in an equine superficial digital flexor (SDF) tendonitis model. We hypothesized intralesional injection of APS would result in superior structural and biomechanical healing. SDF tendonitis was induced in both forelimbs of eight horses using collagenase injection. One forelimb was randomly assigned to receive an intralesional injection of APS, while the other was injected with saline. Ultrasonographic examinations were performed at weeks −1, 0, 2, 4, 8, and 12 following treatment. At 12 weeks, horses were euthanized and SDF samples harvested. Histologic evaluation, biomechanical testing, gene expression analysis, total glycosaminoglycan (GAG) and total DNA quantification were performed. Collagen type III (COL3A1) expression was significantly higher (p = 0.028) in saline treated tendon than in normal tendon. Otherwise, there were no significant differences in gene expression. There were no significant differences in histologic or ultrasonographic scores between groups. Mean total DNA content was significantly higher (p = 0.024) in saline treated tendons than normal tendons, whereas total DNA content was not significantly different between APS treated tendon and normal tendon. Elastic modulus was higher in APS treated than saline treated tendon, but the difference was not significant. Reduced expression of COL3A1 in APS treated tendon may indicate superior healing. Increased total DNA content in saline treated tendon may indicate ongoing healing processes, vs. APS treated tendons which may be in the later stages of healing. Limitations include a relatively short study period and inconsistency in size and severity of induced lesions. Intralesional injection of APS resulted in some improvements in healing characteristics.
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Affiliation(s)
- Angela M Gaesser
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States
| | - Claire Underwood
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States
| | - Renata L Linardi
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States
| | - Kayla M Even
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States
| | - Virginia B Reef
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States
| | - Snehal S Shetye
- McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Robert L Mauck
- McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | | | - Julie B Engiles
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States.,Department of Pathobiology, New Bolton Center, School of Veterinary Medicine, University of Pennyslvania, Philadelphia, PA, United States
| | - Kyla F Ortved
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States
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31
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Species variations in tenocytes' response to inflammation require careful selection of animal models for tendon research. Sci Rep 2021; 11:12451. [PMID: 34127759 PMCID: PMC8203623 DOI: 10.1038/s41598-021-91914-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 05/24/2021] [Indexed: 01/23/2023] Open
Abstract
For research on tendon injury, many different animal models are utilized; however, the extent to which these species simulate the clinical condition and disease pathophysiology has not yet been critically evaluated. Considering the importance of inflammation in tendon disease, this study compared the cellular and molecular features of inflammation in tenocytes of humans and four common model species (mouse, rat, sheep, and horse). While mouse and rat tenocytes most closely equalled human tenocytes’ low proliferation capacity and the negligible effect of inflammation on proliferation, the wound closure speed of humans was best approximated by rats and horses. The overall gene expression of human tenocytes was most similar to mice under healthy, to horses under transient and to sheep under constant inflammatory conditions. Humans were best matched by mice and horses in their tendon marker and collagen expression, by horses in extracellular matrix remodelling genes, and by rats in inflammatory mediators. As no single animal model perfectly replicates the clinical condition and sufficiently emulates human tenocytes, fit-for-purpose selection of the model species for each specific research question and combination of data from multiple species will be essential to optimize translational predictive validity.
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Leek CC, Soulas JM, Sullivan AL, Killian ML. Using tools in mechanobiology to repair tendons. ACTA ACUST UNITED AC 2021; 1:31-40. [PMID: 33585822 DOI: 10.1007/s43152-020-00005-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Purpose of review The purpose of this review is to describe the mechanobiological mechanisms of tendon repair as well as outline current and emerging tools in mechanobiology that might be useful for improving tendon healing and regeneration. Over 30 million musculoskeletal injuries are reported in the US per year and nearly 50% involve soft tissue injuries to tendons and ligaments. Yet current therapeutic strategies for treating tendon injuries are not always successful in regenerating and returning function of the healing tendon. Recent findings The use of rehabilitative strategies to control the motion and transmission of mechanical loads to repairing tendons following surgical reattachment is beneficial for some, but not all, tendon repairs. Scaffolds that are designed to recapitulate properties of developing tissues show potential to guide the mechanical and biological healing of tendon following rupture. The incorporation of biomaterials to control alignment and reintegration, as well as promote scar-less healing, are also promising. Improving our understanding of damage thresholds for resident cells and how these cells respond to bioelectrical cues may offer promising steps forward in the field of tendon regeneration. Summary The field of orthopaedics continues to advance and improve with the development of regenerative approaches for musculoskeletal injuries, especially for tendon, and deeper exploration in this area will lead to improved clinical outcomes.
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Affiliation(s)
- Connor C Leek
- College of Engineering, Department of Biomedical Engineering, 5 Innovation Way, Suite 200, University of Delaware, Newark, Delaware 19716
| | - Jaclyn M Soulas
- College of Engineering, Department of Biomedical Engineering, 5 Innovation Way, Suite 200, University of Delaware, Newark, Delaware 19716.,College of Agriculture and Natural Resources, Department of Animal Biosciences, 531 South College Avenue, University of Delaware, Newark, Delaware 19716
| | - Anna Lia Sullivan
- College of Engineering, Department of Biomedical Engineering, 5 Innovation Way, Suite 200, University of Delaware, Newark, Delaware 19716.,College of Agriculture and Natural Resources, Department of Animal Biosciences, 531 South College Avenue, University of Delaware, Newark, Delaware 19716
| | - Megan L Killian
- College of Engineering, Department of Biomedical Engineering, 5 Innovation Way, Suite 200, University of Delaware, Newark, Delaware 19716.,College of Medicine, Department of Orthopaedic Surgery, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, Michigan 48109
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Carroll CC, Chemelewski K, Patel SH, Curtis D. Acute-Onset Achilles Tendon Pain and Swelling Treated with an Amniotic Fluid-Derived Allograft: A Case Study. J Am Podiatr Med Assoc 2021; 111:462605. [PMID: 33690801 DOI: 10.7547/20-005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Tendinopathies are common musculoskeletal disorders that often develop because of chronic loading and failed healing. Tendinopathy related to systemic inflammation has been less extensively examined. Furthermore, although the use of biological agents to treat tendinopathies continues to gain popularity, the use of amniotic fluid-derived allografts in outpatient settings to resolve tendinopathies requires further evaluation. METHODS The focus of this case report is a 25-year-old man who presented for a second opinion, having been diagnosed with Haglund deformity and Achilles tendinopathy. At the time of presentation, he complained of 10 of 10 pain to the right Achilles tendon. He was treating the injury conservatively with intermittent use of a controlled ankle motion boot and working with physiotherapy for approximately 5 months before presentation. Diagnostic ultrasound along with magnetic resonance imaging indicated distal thickening of the Achilles tendon, substantial fluid and edema in the Kager fat pad, and retrocalcaneal erosions with bursitis. Conservative management did not resolve the symptoms. As an alternative to surgery, the patient elected to undergo an Achilles tendon injection of an amniotic fluid-derived allograft. Before and after the initial injection, a microdialysis catheter was inserted into the Achilles peritendinous space to sample local levels of extracellular matrix enzymes and growth factors important for tendon remodeling. The patient received considerable relief with the initial injection, but did not return to full strength. Over the subsequent 8 weeks, the patient was followed closely and was able to return to daily activities with minimal pain. He was not able to return to a more active lifestyle without further Achilles pain, so a second amniotic fluid-derived allograft injection was performed 8 weeks after the initial injection. RESULTS Injection of the initial allograft resulted in significant improvement, but not complete resolution of pain and swelling. Microdialysis findings suggested a reduction in peritendinous levels of the cytokine interlukin-6 in addition to changes in extracellular matrix regulatory enzymes. After 8 weeks of additional conservative therapy and a second injection, no further improvement in pain was noted. CONCLUSIONS Based on the clinical improvement of symptoms in this individual and the changes seen with microdialysis methodology, the authors find the use of amniotic fluid-derived allograft injection for treatment of Achilles pain in this patient to be a viable treatment. Additional comorbidities of systemic inflammatory polyarthritis and possible seronegative disease were addressed after rheumatology consultation with a variety of medications that provided the patient additional relief of his symptoms. The patient ultimately moved and was lost to further follow-up.
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Siadat SM, Zamboulis DE, Thorpe CT, Ruberti JW, Connizzo BK. Tendon Extracellular Matrix Assembly, Maintenance and Dysregulation Throughout Life. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:45-103. [PMID: 34807415 DOI: 10.1007/978-3-030-80614-9_3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
In his Lissner Award medal lecture in 2000, Stephen Cowin asked the question: "How is a tissue built?" It is not a new question, but it remains as relevant today as it did when it was asked 20 years ago. In fact, research on the organization and development of tissue structure has been a primary focus of tendon and ligament research for over two centuries. The tendon extracellular matrix (ECM) is critical to overall tissue function; it gives the tissue its unique mechanical properties, exhibiting complex non-linear responses, viscoelasticity and flow mechanisms, excellent energy storage and fatigue resistance. This matrix also creates a unique microenvironment for resident cells, allowing cells to maintain their phenotype and translate mechanical and chemical signals into biological responses. Importantly, this architecture is constantly remodeled by local cell populations in response to changing biochemical (systemic and local disease or injury) and mechanical (exercise, disuse, and overuse) stimuli. Here, we review the current understanding of matrix remodeling throughout life, focusing on formation and assembly during the postnatal period, maintenance and homeostasis during adulthood, and changes to homeostasis in natural aging. We also discuss advances in model systems and novel tools for studying collagen and non-collagenous matrix remodeling throughout life, and finally conclude by identifying key questions that have yet to be answered.
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Affiliation(s)
| | - Danae E Zamboulis
- Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Chavaunne T Thorpe
- Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK
| | - Jeffrey W Ruberti
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Brianne K Connizzo
- Department of Biomedical Engineering, Boston University, Boston, MA, USA.
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Lu PP, Chen MH, Dai GC, Li YJ, Shi L, Rui YF. Understanding cellular and molecular mechanisms of pathogenesis of diabetic tendinopathy. World J Stem Cells 2020; 12:1255-1275. [PMID: 33312397 PMCID: PMC7705468 DOI: 10.4252/wjsc.v12.i11.1255] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/19/2020] [Accepted: 09/10/2020] [Indexed: 02/06/2023] Open
Abstract
There is accumulating evidence of an increased incidence of tendon disorders in people with diabetes mellitus. Diabetic tendinopathy is an important cause of chronic pain, restricted activity, and even tendon rupture in individuals. Tenocytes and tendon stem/progenitor cells (TSPCs) are the dominant cellular components associated with tendon homeostasis, maintenance, remodeling, and repair. Some previous studies have shown alterations in tenocytes and TSPCs in high glucose or diabetic conditions that might cause structural and functional variations in diabetic tendons and even accelerate the development and progression of diabetic tendinopathy. In this review, the biomechanical properties and histopathological changes in diabetic tendons are described. Then, the cellular and molecular alterations in both tenocytes and TSPCs are summarized, and the underlying mechanisms involved are also analyzed. A better understanding of the underlying cellular and molecular pathogenesis of diabetic tendinopathy would provide new insight for the exploration and development of effective therapeutics.
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Affiliation(s)
- Pan-Pan Lu
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing 210009, Jiangsu Province, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Min-Hao Chen
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing 210009, Jiangsu Province, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Guang-Chun Dai
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing 210009, Jiangsu Province, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ying-Juan Li
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- China Orthopedic Regenerative Medicine Group, Hangzhou 310000, Zhejiang Province, China
| | - Liu Shi
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing 210009, Jiangsu Province, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- China Orthopedic Regenerative Medicine Group, Hangzhou 310000, Zhejiang Province, China
| | - Yun-Feng Rui
- Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing 210009, Jiangsu Province, China
- Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- China Orthopedic Regenerative Medicine Group, Hangzhou 310000, Zhejiang Province, China.
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Sánchez-Sánchez JL, Calderón-Díez L, Herrero-Turrión J, Méndez-Sánchez R, Arias-Buría JL, Fernández-de-las-Peñas C. Changes in Gene Expression Associated with Collagen Regeneration and Remodeling of Extracellular Matrix after Percutaneous Electrolysis on Collagenase-Induced Achilles Tendinopathy in an Experimental Animal Model: A Pilot Study. J Clin Med 2020; 9:jcm9103316. [PMID: 33076550 PMCID: PMC7602800 DOI: 10.3390/jcm9103316] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/21/2020] [Accepted: 10/12/2020] [Indexed: 01/04/2023] Open
Abstract
Percutaneous electrolysis is an emerging intervention proposed for the management of tendinopathies. Tendon pathology is characterized by a significant cell response to injury and gene expression. No study investigating changes in expression of those genes associated with collagen regeneration and remodeling of extracellular matrix has been conducted. The aim of this pilot study was to investigate gene expression changes after the application of percutaneous electrolysis on experimentally induced Achilles tendinopathy with collagenase injection in an animal model. Fifteen Sprague Dawley male rats were randomly divided into three different groups (no treatment vs. percutaneous electrolysis vs. needling). Achilles tendinopathy was experimentally induced with a single bolus of collagenase injection. Interventions consisted of 3 sessions (one per week) of percutaneous electrolysis or just needling. The rats were euthanized, and molecular expression of genes involved in tendon repair and remodeling, e.g., Cox2, Mmp2, Mmp9, Col1a1, Col3a1, Vegf and Scx, was examined at 28 days after injury. Histological tissue changes were determined with hematoxylin–eosin and safranin O analyses. The images of hematoxylin–eosin and Safranin O tissue images revealed that collagenase injection induced histological changes compatible with a tendinopathy. No further histological changes were observed after the application of percutaneous electrolysis or needling. A significant increase in molecular expression of Cox2, Mmp9 and Vegf genes was observed in Achilles tendons treated with percutaneous electrolysis to a greater extent than after just needling. The expression of Mmp2, Col1a1, Col3a1, or Scx genes also increased, but did not reach statistical significance. This animal study demonstrated that percutaneous electrolysis applied on an experimentally induced Achilles tendinopathy model could increase the expression of some genes associated with collagen regeneration and remodeling of extracellular matrix. The observed gene overexpression was higher with percutaneous electrolysis than with just needling.
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Affiliation(s)
- José Luis Sánchez-Sánchez
- Department of Physical Therapy, Universidad de Salamanca, 37007 Salamanca, Spain; (J.L.S.-S.); (L.C.-D.); (R.M.-S.)
| | - Laura Calderón-Díez
- Department of Physical Therapy, Universidad de Salamanca, 37007 Salamanca, Spain; (J.L.S.-S.); (L.C.-D.); (R.M.-S.)
- Physical Therapy Department, Mutua Accidentes Laborales, FREMAP, 37007 Salamanca, Spain
| | - Javier Herrero-Turrión
- Instituto de Neurociencias de Castilla y León, Universidad de Salamanca, 37007 Salamanca, Spain;
- Instituto Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, 37007 Salamanca, Spain
| | - Roberto Méndez-Sánchez
- Department of Physical Therapy, Universidad de Salamanca, 37007 Salamanca, Spain; (J.L.S.-S.); (L.C.-D.); (R.M.-S.)
| | - José L. Arias-Buría
- Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Universidad Rey Juan Carlos (URJC), Alcorcón, 28922 Madrid, Spain;
- Cátedra Institucional en Docencia, Clínica e Investigación en Fisioterapia: Terapia Manual, Punción Seca y Ejercicio Terapéutico, Universidad Rey Juan Carlos, Alcorcón, 28922 Madrid, Spain
| | - César Fernández-de-las-Peñas
- Department of Physical Therapy, Occupational Therapy, Physical Medicine and Rehabilitation, Universidad Rey Juan Carlos (URJC), Alcorcón, 28922 Madrid, Spain;
- Cátedra Institucional en Docencia, Clínica e Investigación en Fisioterapia: Terapia Manual, Punción Seca y Ejercicio Terapéutico, Universidad Rey Juan Carlos, Alcorcón, 28922 Madrid, Spain
- Correspondence: ; Tel.: +34-91-488-88-84
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Darrieutort-Laffite C, Soslowsky LJ, Le Goff B. Molecular and Structural Effects of Percutaneous Interventions in Chronic Achilles Tendinopathy. Int J Mol Sci 2020; 21:ijms21197000. [PMID: 32977533 PMCID: PMC7582801 DOI: 10.3390/ijms21197000] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/08/2020] [Accepted: 09/15/2020] [Indexed: 12/11/2022] Open
Abstract
Achilles tendinopathy (AT) is a common problem, especially in people of working age, as well as in the elderly. Although the pathogenesis of tendinopathy is better known, therapeutic management of AT remains challenging. Various percutaneous treatments have been applied to tendon lesions: e.g., injectable treatments, platelet-rich plasma (PRP), corticosteroids, stem cells, MMP inhibitors, and anti-angiogenic agents), as well as percutaneous procedures without any injection (percutaneous soft tissue release and dry needling). In this review, we will describe and comment on data about the molecular and structural effects of these treatments obtained in vitro and in vivo and report their efficacy in clinical trials. Local treatments have some impact on neovascularization, inflammation or tissue remodeling in animal models, but evidence from clinical trials remains too weak to establish an accurate management plan, and further studies will be necessary to evaluate their value.
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Affiliation(s)
- Christelle Darrieutort-Laffite
- Rheumatology Department, Nantes University Hospital, 44000 Nantes, France;
- INSERM UMR1238, Bone Sarcoma and Remodeling of Calcified Tissue, Nantes University, 44000 Nantes, France
- Correspondence: ; Tel.: +33-2-40-08-48-01
| | - Louis J. Soslowsky
- McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA 19401-6081, USA;
| | - Benoit Le Goff
- Rheumatology Department, Nantes University Hospital, 44000 Nantes, France;
- INSERM UMR1238, Bone Sarcoma and Remodeling of Calcified Tissue, Nantes University, 44000 Nantes, France
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Citeroni MR, Ciardulli MC, Russo V, Della Porta G, Mauro A, El Khatib M, Di Mattia M, Galesso D, Barbera C, Forsyth NR, Maffulli N, Barboni B. In Vitro Innovation of Tendon Tissue Engineering Strategies. Int J Mol Sci 2020; 21:E6726. [PMID: 32937830 PMCID: PMC7555358 DOI: 10.3390/ijms21186726] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/06/2020] [Accepted: 09/07/2020] [Indexed: 12/12/2022] Open
Abstract
Tendinopathy is the term used to refer to tendon disorders. Spontaneous adult tendon healing results in scar tissue formation and fibrosis with suboptimal biomechanical properties, often resulting in poor and painful mobility. The biomechanical properties of the tissue are negatively affected. Adult tendons have a limited natural healing capacity, and often respond poorly to current treatments that frequently are focused on exercise, drug delivery, and surgical procedures. Therefore, it is of great importance to identify key molecular and cellular processes involved in the progression of tendinopathies to develop effective therapeutic strategies and drive the tissue toward regeneration. To treat tendon diseases and support tendon regeneration, cell-based therapy as well as tissue engineering approaches are considered options, though none can yet be considered conclusive in their reproduction of a safe and successful long-term solution for full microarchitecture and biomechanical tissue recovery. In vitro differentiation techniques are not yet fully validated. This review aims to compare different available tendon in vitro differentiation strategies to clarify the state of art regarding the differentiation process.
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Affiliation(s)
- Maria Rita Citeroni
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Maria Camilla Ciardulli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy; (M.C.C.); (G.D.P.); (N.M.)
| | - Valentina Russo
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Giovanna Della Porta
- Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy; (M.C.C.); (G.D.P.); (N.M.)
- Interdepartment Centre BIONAM, Università di Salerno, via Giovanni Paolo I, 84084 Fisciano (SA), Italy
| | - Annunziata Mauro
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Mohammad El Khatib
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Miriam Di Mattia
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Devis Galesso
- Fidia Farmaceutici S.p.A., via Ponte della Fabbrica 3/A, 35031 Abano Terme (PD), Italy; (D.G.); (C.B.)
| | - Carlo Barbera
- Fidia Farmaceutici S.p.A., via Ponte della Fabbrica 3/A, 35031 Abano Terme (PD), Italy; (D.G.); (C.B.)
| | - Nicholas R. Forsyth
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Thornburrow Drive, Stoke on Trent ST4 7QB, UK;
| | - Nicola Maffulli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy; (M.C.C.); (G.D.P.); (N.M.)
- Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, Via San Leonardo 1, 84131 Salerno, Italy
- Centre for Sports and Exercise Medicine, Barts and The London School of Medicine and Dentistry, Mile End Hospital, Queen Mary University of London, 275 Bancroft Road, London E1 4DG, UK
- School of Pharmacy and Bioengineering, Keele University School of Medicine, Thornburrow Drive, Stoke on Trent ST5 5BG, UK
| | - Barbara Barboni
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
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Matrix Metalloproteinase Genes ( MMP1, MMP10, MMP12) on Chromosome 11q22 and the Risk of Non-Contact Anterior Cruciate Ligament Ruptures. Genes (Basel) 2020; 11:genes11070766. [PMID: 32650441 PMCID: PMC7397146 DOI: 10.3390/genes11070766] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/30/2020] [Accepted: 07/06/2020] [Indexed: 12/13/2022] Open
Abstract
Background: Sequence variants within the matrix metalloproteinases genes remain plausible biological candidates for further investigation of anterior cruciate ligament (ACL) rupture risk. The aim of the present study was to establish whether variants within the MMP1 (rs1799750, ->G), MMP10 (rs486055, C > T) and MMP12 (rs2276109, T > C) genes were associated with non-contact ACL rupture in a Polish cohort. Methods: The unrelated, self-reported Polish Caucasian participants consisted of 228 (157 male) individuals with primary non-contact ACL rupture and 202 (117 male) participants without any history of ACL rupture. All samples were genotyped in duplicate using the Applied Biosystems TaqMan® methodology. The statistical analyses were involved in determining the distribution of genotype and allele frequencies for the investigated polymorphisms between the diagnostic groups. Furthermore, pseudo-haplotypes were constructed to assess possible gene–gene interactions. Results: All genotype frequencies in the ACL rupture and control groups conformed to Hardy Weinberg Equilibrium expectations. None of the polymorphisms were associated with risk of non-contact ACL rupture under the codominant, dominant, recessive and over-dominant genetic models. Likewise, no genotype–genotype combinations inferred as “haplotypes” as a proxy of gene–gene interactions were associated with the risk of non-contact ACL ruptures. Conclusions: Despite the fact that the current study did not support existing evidence suggesting that variants within the MMP1, MMP10, and MMP12 genes influence non-contact ACL rupture risk, future work should include high-throughput sequencing technologies to identify potential targeted polymorphisms to fully characterize the 11q22 region with susceptibility to non-contact ACL rupture susceptibility in a Polish cohort.
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Huang YM, Lin YC, Chen CY, Hsieh YY, Liaw CK, Huang SW, Tsuang YH, Chen CH, Lin FH. Thermosensitive Chitosan-Gelatin-Glycerol Phosphate Hydrogels as Collagenase Carrier for Tendon-Bone Healing in a Rabbit Model. Polymers (Basel) 2020; 12:polym12020436. [PMID: 32069799 PMCID: PMC7077724 DOI: 10.3390/polym12020436] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 01/27/2020] [Accepted: 02/08/2020] [Indexed: 11/16/2022] Open
Abstract
Healing of an anterior cruciate ligament graft in bone tunnel yields weaker fibrous scar tissue, which may prolong an already prolonged healing process within the tendon-bone interface. In this study, gelatin molecules were added to thermosensitive chitosan/β-glycerol phosphate disodium salt hydrogels to form chitosan/gelatin/β-glycerol phosphate (C/G/GP) hydrogels, which were applied to 0.1 mg/mL collagenase carrier in the tendon-bone junction. New Zealand white rabbit's long digital extensor tendon was detached and translated into a 2.5-mm diameter tibial plateau tunnel. Thirty-six rabbits underwent bilateral surgery and hydrogel injection treatment with and without collagenase. Histological analyses revealed early healing and more bone formation at the tendon-bone interface after collagenase partial digestion. The area of metachromasia significantly increased in both 4-week and 8-week groups after collagenase treatment (p < 0.01). Micro computed tomography showed a significant increase in total bone volume and bone volume/tissue volume in the 8 weeks after collagenase treatment, compared with the control group. Load-to-failure was significantly higher in the treated group at 8 weeks (23.8 ± 8.13 N vs 14.3 ± 3.9 N; p = 0.008). Treatment with collagenase digestion resulted in a 66% increase in pull-out strength. In conclusion, injection of C/G/GP hydrogel with collagenase improves tendon-to-bone healing in a rabbit model.
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Affiliation(s)
- Yu-Min Huang
- Department of Biomedical Engineering, National Taiwan University, Taipei 100, Taiwan; (Y.-M.H.); (S.-W.H.)
- Department of Orthopedics, Shuang Ho Hospital, Taipei Medical University, Taipei 100, Taiwan; (Y.-C.L.); (C.-Y.C.); (Y.-Y.H.); (C.-K.L.); (Y.-H.T.)
- Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 100, Taiwan
| | - Yi-Cheng Lin
- Department of Orthopedics, Shuang Ho Hospital, Taipei Medical University, Taipei 100, Taiwan; (Y.-C.L.); (C.-Y.C.); (Y.-Y.H.); (C.-K.L.); (Y.-H.T.)
- Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 100, Taiwan
| | - Chih-Yu Chen
- Department of Orthopedics, Shuang Ho Hospital, Taipei Medical University, Taipei 100, Taiwan; (Y.-C.L.); (C.-Y.C.); (Y.-Y.H.); (C.-K.L.); (Y.-H.T.)
- Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 100, Taiwan
| | - Yueh-Ying Hsieh
- Department of Orthopedics, Shuang Ho Hospital, Taipei Medical University, Taipei 100, Taiwan; (Y.-C.L.); (C.-Y.C.); (Y.-Y.H.); (C.-K.L.); (Y.-H.T.)
- Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 100, Taiwan
| | - Chen-Kun Liaw
- Department of Orthopedics, Shuang Ho Hospital, Taipei Medical University, Taipei 100, Taiwan; (Y.-C.L.); (C.-Y.C.); (Y.-Y.H.); (C.-K.L.); (Y.-H.T.)
- Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 100, Taiwan
| | - Shu-Wei Huang
- Department of Biomedical Engineering, National Taiwan University, Taipei 100, Taiwan; (Y.-M.H.); (S.-W.H.)
| | - Yang-Hwei Tsuang
- Department of Orthopedics, Shuang Ho Hospital, Taipei Medical University, Taipei 100, Taiwan; (Y.-C.L.); (C.-Y.C.); (Y.-Y.H.); (C.-K.L.); (Y.-H.T.)
- Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 100, Taiwan
| | - Chih-Hwa Chen
- Department of Orthopedics, Taipei Medical University – Shuang Ho Hospital, School of Medicine, College of Medicine, School of Biomedical Engineering, College of Biomedical Engineering, Research Center of Biomedical Device, Taipei Medical University, Taipei 100, Taiwan;
| | - Feng-Huei Lin
- Department of Biomedical Engineering, National Taiwan University, Taipei 100, Taiwan; (Y.-M.H.); (S.-W.H.)
- Institute of Biomedical Engineering & Nanomedicine, National Health Research Institutes, Miaoli County 360, Taiwan
- Correspondence: ; Tel.: +886-2-2732-0443
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Flexor Tendon: Development, Healing, Adhesion Formation, and Contributing Growth Factors. Plast Reconstr Surg 2020; 144:639e-647e. [PMID: 31568303 DOI: 10.1097/prs.0000000000006048] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Management of flexor tendon injuries of the hand remains a major clinical problem. Even with intricate repair, adhesion formation remains a common complication. Significant progress has been made to better understand the mechanisms of healing and adhesion formation. However, there has been slow progress in the clinical prevention and reversal of flexor tendon adhesions. The goal of this article is to discuss recent literature relating to tendon development, tendon healing, and adhesion formation to identify areas in need of further research. Additional research is needed to understand and compare the molecular, cellular, and genetic mechanisms involved in flexor tendon morphogenesis, postoperative healing, and mechanical loading. Such knowledge is critical to determine how to improve repair outcomes and identify new therapeutic strategies to promote tissue regeneration and prevent adhesion formation.
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Steinmann S, Pfeifer CG, Brochhausen C, Docheva D. Spectrum of Tendon Pathologies: Triggers, Trails and End-State. Int J Mol Sci 2020; 21:ijms21030844. [PMID: 32013018 PMCID: PMC7037288 DOI: 10.3390/ijms21030844] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 01/18/2020] [Accepted: 01/24/2020] [Indexed: 12/31/2022] Open
Abstract
The biggest compartment of the musculoskeletal system is the tendons and ligaments. In particular, tendons are dense tissues connecting muscle to bone that are critical for the integrity, function and locomotion of this system. Due to the increasing age of our society and the overall rise in engagement in extreme and overuse sports, there is a growing prevalence of tendinopathies. Despite the recent advances in tendon research and due to difficult early diagnosis, a multitude of risk factors and vague understanding of the underlying biological mechanisms involved in the progression of tendon injuries, the toolbox of treatment strategies remains limited and non-satisfactory. This review is designed to summarize the current knowledge of triggers, trails and end state of tendinopathies.
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Affiliation(s)
- Sara Steinmann
- Experimental Trauma Surgery, Department of Trauma Surgery, University Medical Center Regensburg, Am Biopark 9, 93053 Regensburg, Germany; (S.S.); (C.G.P.)
| | - Christian G. Pfeifer
- Experimental Trauma Surgery, Department of Trauma Surgery, University Medical Center Regensburg, Am Biopark 9, 93053 Regensburg, Germany; (S.S.); (C.G.P.)
- Department of Trauma Surgery, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Christoph Brochhausen
- Institute of Pathology, University Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany;
| | - Denitsa Docheva
- Experimental Trauma Surgery, Department of Trauma Surgery, University Medical Center Regensburg, Am Biopark 9, 93053 Regensburg, Germany; (S.S.); (C.G.P.)
- Department of Medical Biology, Medical University-Plovdiv, 15A Vassil Aprilov Blvd., 4002 Plovdiv, Bulgaria
- Correspondence: ; Tel.: +49 941 943-1605
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Wunderli SL, Blache U, Beretta Piccoli A, Niederöst B, Holenstein CN, Passini FS, Silván U, Bundgaard L, Auf dem Keller U, Snedeker JG. Tendon response to matrix unloading is determined by the patho-physiological niche. Matrix Biol 2020; 89:11-26. [PMID: 31917255 DOI: 10.1016/j.matbio.2019.12.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 12/17/2019] [Accepted: 12/17/2019] [Indexed: 12/20/2022]
Abstract
Although the molecular mechanisms behind tendon disease remain obscure, aberrant stromal matrix turnover and tissue hypervascularity are known hallmarks of advanced tendinopathy. We harness a tendon explant model to unwind complex cross-talk between the stromal and vascular tissue compartments. We identify the hypervascular tendon niche as a state-switch that gates degenerative matrix remodeling within the tissue stroma. Here pathological conditions resembling hypervascular tendon disease provoke rapid cell-mediated tissue breakdown upon mechanical unloading, in contrast to unloaded tendons that remain functionally stable in physiological low-oxygen/-temperature niches. Analyses of the stromal tissue transcriptome and secretome reveal that a stromal niche with elevated tissue oxygenation and temperature drives a ROS mediated cellular stress response that leads to adoption of an immune-modulatory phenotype within the degrading stromal tissue. Degradomic analysis further reveals a surprisingly rich set of active matrix proteases behind the progressive loss of tissue mechanics. We conclude that the tendon stromal compartment responds to aberrant mechanical unloading in a manner that is highly dependent on the vascular niche, with ROS gating a complex proteolytic breakdown of the functional collagen backbone.
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Affiliation(s)
- Stefania L Wunderli
- University Hospital Balgrist, University of Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Switzerland
| | - Ulrich Blache
- University Hospital Balgrist, University of Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Switzerland
| | - Agnese Beretta Piccoli
- University Hospital Balgrist, University of Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Switzerland
| | - Barbara Niederöst
- University Hospital Balgrist, University of Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Switzerland
| | - Claude N Holenstein
- University Hospital Balgrist, University of Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Switzerland
| | - Fabian S Passini
- University Hospital Balgrist, University of Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Switzerland
| | - Unai Silván
- University Hospital Balgrist, University of Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Switzerland
| | - Louise Bundgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Denmark
| | - Ulrich Auf dem Keller
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Denmark
| | - Jess G Snedeker
- University Hospital Balgrist, University of Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Switzerland.
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44
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Ryan CNM, Zeugolis DI. Engineering the Tenogenic Niche In Vitro with Microenvironmental Tools. ADVANCED THERAPEUTICS 2019. [DOI: 10.1002/adtp.201900072] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Christina N. M. Ryan
- Regenerative, Modular and Developmental Engineering LaboratoryBiomedical Sciences BuildingNational University of Ireland Galway Galway H91 W2TY Ireland
- Science Foundation Ireland, Centre for Research in Medical DevicesBiomedical Sciences BuildingNational University of Ireland Galway Galway H91 W2TY Ireland
| | - Dimitrios I. Zeugolis
- Regenerative, Modular and Developmental Engineering LaboratoryBiomedical Sciences BuildingNational University of Ireland Galway Galway H91 W2TY Ireland
- Science Foundation Ireland, Centre for Research in Medical DevicesBiomedical Sciences BuildingNational University of Ireland Galway Galway H91 W2TY Ireland
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45
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Tran PHT, Malmgaard-Clausen NM, Puggaard RS, Svensson RB, Nybing JD, Hansen P, Schjerling P, Zinglersen AH, Couppé C, Boesen M, Magnusson SP, Kjaer M. Early development of tendinopathy in humans: Sequence of pathological changes in structure and tissue turnover signaling. FASEB J 2019; 34:776-788. [PMID: 31914656 DOI: 10.1096/fj.201901309r] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 09/09/2019] [Accepted: 10/23/2019] [Indexed: 02/06/2023]
Abstract
Overloading of tendon tissue with resulting chronic pain (tendinopathy) is a common disorder in occupational-, leisure- and sports-activity, but its pathogenesis remains poorly understood. To investigate the very early phase of tendinopathy, Achilles and patellar tendons were investigated in 200 physically active patients and 50 healthy control persons. Patients were divided into three groups: symptoms for 0-1 months (T1), 1-2 months (T2) or 2-3 months (T3). Tendinopathic Achilles tendon cross-sectional area determined by ultrasonography (US) was ~25% larger than in healthy control persons. Both Achilles and patellar anterior-posterior diameter were elevated in tendinopathy, and only later in Achilles was the width increased. Increased tendon size was accompanied by an increase in hypervascularization (US Doppler flow) without any change in mRNA for angiogenic factors. From patellar biopsies taken bilaterally, mRNA for most growth factors and tendon components remained unchanged (except for TGF-beta1 and substance-P) in early tendinopathy. Tendon stiffness remained unaltered over the first three months of tendinopathy and was similar to the asymptomatic contra-lateral tendon. In conclusion, this suggests that tendinopathy pathogenesis represents a disturbed tissue homeostasis with fluid accumulation. The disturbance is likely induced by repeated mechanical overloading rather than a partial rupture of the tendon.
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Affiliation(s)
- Peter H T Tran
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.,Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nikolaj M Malmgaard-Clausen
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.,Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rikke S Puggaard
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.,Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - René B Svensson
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.,Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Janus D Nybing
- Department of Radiology, Bispebjerg-Frederiksberg Hospital, Frederiksberg, Denmark
| | - Philip Hansen
- Department of Radiology, Bispebjerg-Frederiksberg Hospital, Frederiksberg, Denmark
| | - Peter Schjerling
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.,Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Amanda H Zinglersen
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.,Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christian Couppé
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.,Department of Physical & Occupational Therapy, Bispebjerg Hospital, Copenhagen, Denmark
| | - Mikael Boesen
- Department of Radiology, Bispebjerg-Frederiksberg Hospital, Frederiksberg, Denmark
| | - S Peter Magnusson
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.,Department of Physical & Occupational Therapy, Bispebjerg Hospital, Copenhagen, Denmark
| | - Michael Kjaer
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.,Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Kang X, Tian B, Zhang L, Ge Z, Zhao Y, Zhang Y. Relationship of common variants in MPP7, TIMP2 and CASP8 genes with the risk of chronic achilles tendinopathy. Sci Rep 2019; 9:17627. [PMID: 31772230 PMCID: PMC6879592 DOI: 10.1038/s41598-019-54097-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 11/08/2019] [Indexed: 11/08/2022] Open
Abstract
Previous etiologic studies have indicated that both environmental and genetic factors play important roles in the occurrence and development of chronic Achilles tendinopathy (AT). A recent study documented the results of the largest genome-wide association study for chronic AT to date, indicating that MPP7, TIMP2 and CASP8 may be involved in the occurrence and development of chronic AT. In this study, we aimed to investigate whether MPP7, TIMP2 and CASP8 were associated with susceptibility to chronic AP in a Han Chinese population. A total of 3,680 study subjects comprised 1,288 chronic AT cases, and 2,392 healthy controls were recruited. Forty-four tag SNPs (7 from CASP8, 20 from MPP7, and 17 from TIMP2) were genotyped in the study. Genetic association analyses were performed at both single marker and haplotype levels. Functional consequences of significant SNPs were examined in the RegulomeDB and GTEx databases. Two SNPs, SNP rs1937810 (OR [95%CI] = 1.20 [1.09-1.32], χ2 = 13.50, P = 0.0002) in MPP7 and rs4789932 (OR [95%CI] = 1.24 [1.12-1.37], χ2 = 17.98, P = 2.23 × 10-5) in TIMP2, were significantly associated with chronic AT. Significant eQTL signals for SNP rs4789932 on TIMP2 were identified in human heart and artery tissues. Our results provide further supportive evidence for the association of the TIMP2 and MPP7 genes with chronic AT, which supports important roles for TIMP2 and MPP7 in the etiology of chronic AT, adding to the current understanding of the susceptibility of chronic AT.
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Affiliation(s)
- Xin Kang
- Department of Orthopedics, the First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China
- Department of Sports Medicine, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Bin Tian
- Department of Sports Medicine, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Liang Zhang
- Department of Sports Medicine, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zhaogang Ge
- Department of Sports Medicine, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yang Zhao
- Department of Sports Medicine, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yingang Zhang
- Department of Orthopedics, the First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China.
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Bisaccia DR, Aicale R, Tarantino D, Peretti GM, Maffulli N. Biological and chemical changes in fluoroquinolone-associated tendinopathies: a systematic review. Br Med Bull 2019; 130:39-49. [PMID: 30811525 DOI: 10.1093/bmb/ldz006] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 01/04/2019] [Accepted: 02/10/2019] [Indexed: 12/29/2022]
Abstract
INTRODUCTION The present systematic review investigates the biological and chemical mechanisms that affect the health and structure of tendons following the use of fluoroquinolones (FQs). SOURCES OF DATA A total of 12 articles were included, organized, and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. AREAS OF AGREEMENT Five mechanisms were identified: arrest of proliferation through a decreased activity of cyclin B, CDK-1, CHK-1, and increased PK-1; decrease tenocytes migration through decreased phosphorylation of FAK; decrease type I collagen metabolism through increased MMP-2; chelate effect on ions that influence epigenetics and several enzymes; fluoroquinolones-induced ROS (radical oxygen species) production in mitochondria. AREAS OF CONTROVERSY There is no definite structure-damage relationship. The dose-effect relationship is unclear. GROWING POINTS Knowing and defining the damage exerted by FQs plays a role in clinical practice, replacing FQs with other antibacterial drugs or using antioxidants to attenuate their pathological effects. AREAS TIMELY FOR DEVELOPING RESEARCH Clinical and basic sciences studies for each FQs are necessary.
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Affiliation(s)
- Domenico Rocco Bisaccia
- Department of Pharmacology, School of Medicine and Surgery, University of Salerno, Salerno, Italy
| | - Rocco Aicale
- Department of Musculoskeletal Disorders, School of Medicine and Surgery, University of Salerno, Salerno, Italy
| | - Domiziano Tarantino
- Department of Musculoskeletal Disorders, School of Medicine and Surgery, University of Salerno, Salerno, Italy
| | - Giuseppe M Peretti
- IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Nicola Maffulli
- Department of Musculoskeletal Disorders, School of Medicine and Surgery, University of Salerno, Salerno, Italy
- Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, Mile End Hospital, 275 Bancroft Road, London, England
- Institute of Science and Technology in Medicine, Keele University School of Medicine, Thornburrow Drive, Stoke on Trent, England
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48
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Tendon and Ligament Injuries in Elite Rugby: The Potential Genetic Influence. Sports (Basel) 2019; 7:sports7060138. [PMID: 31167482 PMCID: PMC6628064 DOI: 10.3390/sports7060138] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 05/29/2019] [Accepted: 05/30/2019] [Indexed: 01/13/2023] Open
Abstract
This article reviews tendon and ligament injury incidence and severity within elite rugby union and rugby league. Furthermore, it discusses the biological makeup of tendons and ligaments and how genetic variation may influence this and predisposition to injury. Elite rugby has one of the highest reported injury incidences of any professional sport. This is likely due to a combination of well-established injury surveillance systems and the characteristics of the game, whereby high-impact body contact frequently occurs, in addition to the high intensity, multispeed and multidirectional nature of play. Some of the most severe of all these injuries are tendon and ligament/joint (non-bone), and therefore, potentially the most debilitating to a player and playing squad across a season or World Cup competition. The aetiology of these injuries is highly multi-factorial, with a growing body of evidence suggesting that some of the inter-individual variability in injury susceptibility may be due to genetic variation. However, little effort has been devoted to the study of genetic injury traits within rugby athletes. Due to a growing understanding of the molecular characteristics underpinning the aetiology of injury, investigating genetic variation within elite rugby is a viable and worthy proposition. Therefore, we propose several single nucleotide polymorphisms within candidate genes of interest; COL1A1, COL3A1, COL5A1, MIR608, MMP3, TIMP2, VEGFA, NID1 and COLGALT1 warrant further study within elite rugby and other invasion sports.
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Tsang AS, Dart AJ, Biasutti SA, Jeffcott LB, Smith MM, Little CB. Effects of tendon injury on uninjured regional tendons in the distal limb: An in-vivo study using an ovine tendinopathy model. PLoS One 2019; 14:e0215830. [PMID: 31013317 PMCID: PMC6478347 DOI: 10.1371/journal.pone.0215830] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 04/09/2019] [Indexed: 12/11/2022] Open
Abstract
Following injury to a tendon little is known about potential for pathology to develop in other regional tendons from overloading or altered function. The aim of this study was to investigate the gene expression and histopathological changes that occur 1) within the deep digital flexor tendon (DDFT) after injury to the superficial digital flexor tendon (SDFT) and 2) within the flexor tendons (SDFT and DDFT) after injury to the extensor tendons. Merino wethers [Ovis aries] (n = 18) were divided into three equal groups and underwent either partial transection of the SDFT, complete transection of the extensor tendons or were left as non-operated controls. Tendons were harvested and sampled regionally for gene expression (real time PCR) and histologic analysis eight weeks after surgery. Transection of the SDFT resulted in increased expression of collagen III, versican, biglycan, lumican and MMP1 (P<0.026 for all genes) within the DDFT. There was no effect of transecting the extensor tendons on the expression of any gene tested in either the SDFT or the DDFT. The DDFT had elevated histopathology scores induced by transection of the SDFT, eight weeks previously. There were minimal histological differences in either the SDFT or DDFT after transection of the extensor tendons. Transection of the SDFT results in a mild, subclinical tendinopathy within the DDFT with potential implications on treatment and rehabilitation of SDFT injuries. Injury to the extensor tendons has minimal measured effect on the SDFT or DDFT.
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Affiliation(s)
- Albert S. Tsang
- Research and Clinical Training Unit, University Veterinary Teaching Hospital, Sydney School of Veterinary Science, Faculty of Science, University of Sydney, Camden, Australia
- * E-mail:
| | - Andrew J. Dart
- Research and Clinical Training Unit, University Veterinary Teaching Hospital, Sydney School of Veterinary Science, Faculty of Science, University of Sydney, Camden, Australia
| | - Sara A. Biasutti
- Research and Clinical Training Unit, University Veterinary Teaching Hospital, Sydney School of Veterinary Science, Faculty of Science, University of Sydney, Camden, Australia
| | - Leo B. Jeffcott
- Research and Clinical Training Unit, University Veterinary Teaching Hospital, Sydney School of Veterinary Science, Faculty of Science, University of Sydney, Camden, Australia
| | - Margaret M. Smith
- Raymond Purves Bone and Joint Research Laboratories, The Kolling Institute, Sydney Medical School, University of Sydney, Sydney, Australia
- The Institute of Bone and Joint Research, Royal North Shore Hospital, Sydney, Australia
| | - Christopher B. Little
- Raymond Purves Bone and Joint Research Laboratories, The Kolling Institute, Sydney Medical School, University of Sydney, Sydney, Australia
- The Institute of Bone and Joint Research, Royal North Shore Hospital, Sydney, Australia
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50
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Rodríguez MA, Sandgren Hochhard K, Vicente A, Liu JX, Pedrosa Domellöf F. Gene expression profile of extraocular muscles following resection strabismus surgery. Exp Eye Res 2019; 182:182-193. [PMID: 30953624 DOI: 10.1016/j.exer.2019.03.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 03/25/2019] [Accepted: 03/28/2019] [Indexed: 10/27/2022]
Abstract
This paper aims to identify key biological processes triggered by resection surgery in the extraocular muscles (EOMs) of a rabbit model of strabismus surgery by studying changes in gene expression. Resection surgery was performed in the superior rectus of 16 rabbits and a group of non-operated rabbits served as control. Muscle samples were collected from groups of four animals 1, 2, 4 and 6 weeks after surgery and processed for RNA-sequencing and immunohistochemistry. We identified a total of 164; 136; 64 and 12 differentially expressed genes 1, 2, 4 and 6 weeks after surgery. Gene Ontology enrichment analysis revealed that differentially expressed genes were involved in biological pathways related to metabolism, response to stimulus mainly related with regulation of immune response, cell cycle and extracellular matrix. A complementary pathway analysis and network analysis performed with Ingenuity Pathway Analysis tool corroborated and completed these findings. Collagen I, fibronectin and versican, evaluated by immunofluorescence, showed that changes at the gene expression level resulted in variation at the protein level. Tenascin-C staining in resected muscles demonstrated the formation of new tendon and myotendinous junctions. These data provide new insights about the biological response of the EOMs to resection surgery and may form the basis for future strategies to improve the outcome of strabismus surgery.
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Affiliation(s)
| | | | - André Vicente
- Department of Clinical Sciences, Ophthalmology, Umeå University, 907 87, Umea, Sweden
| | - Jing-Xia Liu
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, 901 87, Umea, Sweden
| | - Fatima Pedrosa Domellöf
- Department of Clinical Sciences, Ophthalmology, Umeå University, 907 87, Umea, Sweden; Department of Integrative Medical Biology, Section for Anatomy, Umeå University, 901 87, Umea, Sweden.
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