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      Animal model for tendinopathy

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          Abstract

          Background

          Tendinopathy is a common motor system disease that leads to pain and reduced function. Despite its prevalence, our mechanistic understanding is incomplete, leading to limited efficacy of treatment options. Animal models contribute significantly to our understanding of tendinopathy and some therapeutic options. However, the inadequacies of animal models are also evident, largely due to differences in anatomical structure and the complexity of human tendinopathy. Different animal models reproduce different aspects of human tendinopathy and are therefore suitable for different scenarios. This review aims to summarize the existing animal models of tendinopathy and to determine the situations in which each model is appropriate for use, including exploring disease mechanisms and evaluating therapeutic effects.

          Methods

          We reviewed relevant literature in the PubMed database from January 2000 to December 2022 using the specific terms ((tendinopathy) OR (tendinitis)) AND (model) AND ((mice) OR (rat) OR (rabbit) OR (lapin) OR (dog) OR (canine) OR (sheep) OR (goat) OR (horse) OR (equine) OR (pig) OR (swine) OR (primate)). This review summarized different methods for establishing animal models of tendinopathy and classified them according to the pathogenesis they simulate. We then discussed the advantages and disadvantages of each model, and based on this, identified the situations in which each model was suitable for application.

          Results

          For studies that aim to study the pathophysiology of tendinopathy, naturally occurring models, treadmill models, subacromial impingement models and metabolic models are ideal. They are closest to the natural process of tendinopathy in humans. For studies that aim to evaluate the efficacy of possible treatments, the selection should be made according to the pathogenesis simulated by the modeling method. Existing tendinopathy models can be classified into six types according to the pathogenesis they simulate: extracellular matrix synthesis-decomposition imbalance, inflammation, oxidative stress, metabolic disorder, traumatism and mechanical load.

          Conclusions

          The critical factor affecting the translational value of research results is whether the selected model is matched with the research purpose. There is no single optimal model for inducing tendinopathy, and researchers must select the model that is most appropriate for the study they are conducting.

          The translational potential of this article

          The critical factor affecting the translational value of research results is whether the animal model used is compatible with the research purpose. This paper provides a rationale and practical guide for the establishment and selection of animal models of tendinopathy, which is helpful to improve the clinical transformation ability of existing models and develop new models.

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          Most cited references198

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          SYRCLE’s risk of bias tool for animal studies

          Background Systematic Reviews (SRs) of experimental animal studies are not yet common practice, but awareness of the merits of conducting such SRs is steadily increasing. As animal intervention studies differ from randomized clinical trials (RCT) in many aspects, the methodology for SRs of clinical trials needs to be adapted and optimized for animal intervention studies. The Cochrane Collaboration developed a Risk of Bias (RoB) tool to establish consistency and avoid discrepancies in assessing the methodological quality of RCTs. A similar initiative is warranted in the field of animal experimentation. Methods We provide an RoB tool for animal intervention studies (SYRCLE’s RoB tool). This tool is based on the Cochrane RoB tool and has been adjusted for aspects of bias that play a specific role in animal intervention studies. To enhance transparency and applicability, we formulated signalling questions to facilitate judgment. Results The resulting RoB tool for animal studies contains 10 entries. These entries are related to selection bias, performance bias, detection bias, attrition bias, reporting bias and other biases. Half these items are in agreement with the items in the Cochrane RoB tool. Most of the variations between the two tools are due to differences in design between RCTs and animal studies. Shortcomings in, or unfamiliarity with, specific aspects of experimental design of animal studies compared to clinical studies also play a role. Conclusions SYRCLE’s RoB tool is an adapted version of the Cochrane RoB tool. Widespread adoption and implementation of this tool will facilitate and improve critical appraisal of evidence from animal studies. This may subsequently enhance the efficiency of translating animal research into clinical practice and increase awareness of the necessity of improving the methodological quality of animal studies.
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            TGF-β: the master regulator of fibrosis.

            Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease (CKD). Inhibition of the TGF-β isoform, TGF-β1, or its downstream signalling pathways substantially limits renal fibrosis in a wide range of disease models whereas overexpression of TGF-β1 induces renal fibrosis. TGF-β1 can induce renal fibrosis via activation of both canonical (Smad-based) and non-canonical (non-Smad-based) signalling pathways, which result in activation of myofibroblasts, excessive production of extracellular matrix (ECM) and inhibition of ECM degradation. The role of Smad proteins in the regulation of fibrosis is complex, with competing profibrotic and antifibrotic actions (including in the regulation of mesenchymal transitioning), and with complex interplay between TGF-β/Smads and other signalling pathways. Studies over the past 5 years have identified additional mechanisms that regulate the action of TGF-β1/Smad signalling in fibrosis, including short and long noncoding RNA molecules and epigenetic modifications of DNA and histone proteins. Although direct targeting of TGF-β1 is unlikely to yield a viable antifibrotic therapy due to the involvement of TGF-β1 in other processes, greater understanding of the various pathways by which TGF-β1 controls fibrosis has identified alternative targets for the development of novel therapeutics to halt this most damaging process in CKD.
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              Toll-Like Receptor Signaling Pathways

              Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-κB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense.
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                Author and article information

                Contributors
                Journal
                J Orthop Translat
                J Orthop Translat
                Journal of Orthopaedic Translation
                Chinese Speaking Orthopaedic Society
                2214-031X
                2214-0328
                14 August 2023
                September 2023
                14 August 2023
                : 42
                : 43-56
                Affiliations
                [a ]Department of Orthopedic Surgery, The Second Affiliated Hospital of Zhejiang University, 310058, Hangzhou, Zhejiang, China
                [b ]Orthopedics Research Institute of Zhejiang University, 310058, Hangzhou City, Zhejiang Province, China
                [c ]Sports Medicine Institute of Zhejiang University, 310058, Hangzhou, Zhejiang, China
                [d ]Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, 315825, Hangzhou, Zhejiang, China
                [e ]Clinical Research Center of Motor System Disease of Zhejiang Province, 315825, Hangzhou, Zhejiang, China
                [f ]Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, 310058, Hangzhou, Zhejiang, China
                [g ]Department of Orthopedics, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Zhejiang University Huzhou Hospital, 313000, Huzhou, Zhejiang, China
                [h ]Department of Orthopedics, Longquan People's Hospital, Zhejiang, 323799, China
                [i ]Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, China
                Author notes
                []Corresponding author. Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, Zhejiang, China. wlshen@ 123456zju.edu.cn
                [∗∗ ]Corresponding author. Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, 310058, Hangzhou, China. Chenxiao-610@ 123456zju.edu.cn
                [∗∗∗ ]Corresponding author. Department of Orthopedics, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Zhejiang University Huzhou Hospital, Huzhou, Zhejiang, 313000, China. ljywn1977@ 123456126.com
                [1]

                These authors contribute equally to this study.

                Article
                S2214-031X(23)00049-9
                10.1016/j.jot.2023.06.005
                10450357
                37637777
                8dc1979f-c841-45af-beab-eed0ee2c2933
                © 2023 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 29 March 2023
                : 18 June 2023
                : 30 June 2023
                Categories
                Review Article

                animal model,tendinopathy,translational research,tendon,pathogenesis

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