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Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 August 2020) | Viewed by 61865

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Prof. Dr. Denitsa Docheva

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Laboratory of Experimental Trauma Surgery, Department of Trauma Surgery, University Regensburg Medical Centre, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
Interests: Tendons and ligaments; tenomodulin; stem/progenitor cells; tissue engineering; in vivo models (pre-clinical and transgene animal models); cell-based therapies
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Dear Colleagues,

In Greek mythology, Achilles, the Greek hero, is almost invulnerable—except for his Achilles heel, whose injury resulted in his death. How could a tendon injury take such a prominent place in Greek mythology? This injury was obviously such a crucial and inexplicable event that it was extensively honored in the legendary Iliad of Homer. Presumably, the ancient Greeks had already asked themselves how it could have happened that the greatest tendon of man could suddenly break, even in a young, vigorous athlete. Tendons are dense connective tissues and critical components for the integrity and function of the musculoskeletal system, as they connect bone to muscle and transmit forces on which locomotion entirely depends. Due to the increasing age of our society and a rise in the engagement of young people in overuse activities or extreme sports, tendon diseases present major clinical and financial challenges in modern medicine. Inevitably, tendinopathies lead to the final stage disease that is tendon rupture, and once this happens, tendon natural healing is slow, often poorly responding to treatments and requiring prolonged rehabilitation in most cases. A major cause of tendon rupture is tendon tissue degeneration, a process that can be considered a failure of matrix adaptation and remodeling because of an imbalance between matrix decomposition and synthesis due to a variety of stresses and mechanical loads. There are three main hypotheses about the cause(s) of tendon degeneration: (1) mechanical overuse (via matrix), (2) neo-vascularization (via exogenous cells), and (3) cell and tissue aging (via endogenous cells). Most likely, all these three triggers cross-talk to and cross-react with one, another ultimately leading to the failure of the whole tendon unit. So far, there have been only a few approved treatments for tendinopathy that are targeted against specific molecular processes, and still, in most cases, there is little to no evidence of therapeutic effectiveness, especially in the long term. Regarding end-stage tendon rupture, there are two main clinical algorithms, namely, subjecting patients to surgical or conservative therapy, as both require months-long periods to achieve mostly partial and rarely full structural and functional tendon reconstitution.

Therefore, this Special Issue aims to embrace studies concentrating on endogenous tendon cells and their governing molecular pathways, the contribution of exogenous cells (vascular, inflammatory, and neuronal), and the significance of niche structural composition and biomechanical properties leading to tendon diseases, as well as studies focusing on novel tendon medicinal and tissue engineering therapeutic approaches with the overall goal to re-define the status quo in the field of tendon disease and therapy.

Prof. Dr. Denitsa Docheva
Guest Editor

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Keywords

tendinopathy
tendon rupture
tendon healing
tendon stem/progenitor cells
inflammation and immune cells
vasculature and innervation
extracellular matrix
biomechanics
medicinal molecular targets
tendon tissue engineering

Published Papers (13 papers)

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Editorial

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4 pages, 196 KiB

Open AccessEditorial

Editorial for Special Issue: Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches

by Denitsa Docheva

Int. J. Mol. Sci. 2020, 21(20), 7454; https://doi.org/10.3390/ijms21207454 - 09 Oct 2020

Viewed by 1425

Abstract

In Greek mythology, Achilles, the Greek hero, is almost invulnerable—except for his Achilles heel, whose injury resulted in his death[...] Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

Research

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15 pages, 3286 KiB

Open AccessArticle

Magnetic Stimulation Drives Macrophage Polarization in Cell to–Cell Communication with IL-1β Primed Tendon Cells

by Adriana Vinhas, Ana F. Almeida, Ana I. Gonçalves, Márcia T. Rodrigues and Manuela E. Gomes

Int. J. Mol. Sci. 2020, 21(15), 5441; https://doi.org/10.3390/ijms21155441 - 30 Jul 2020

Cited by 21 | Viewed by 3262

Abstract

Inflammation is part of the natural healing response, but it has been simultaneously associated with tendon disorders, as persistent inflammatory events contribute to physiological changes that compromise tendon functions. The cellular interactions within a niche are extremely important for healing. While human tendon cells (hTDCs) are responsible for the maintenance of tendon matrix and turnover, macrophages regulate healing switching their functional phenotype to environmental stimuli. Thus, insights on the hTDCs and macrophages interactions can provide fundamental contributions on tendon repair mechanisms and on the inflammatory inputs in tendon disorders. We explored the crosstalk between macrophages and hTDCs using co-culture approaches in which hTDCs were previously stimulated with IL-1β. The potential modulatory effect of the pulsed electromagnetic field (PEMF) in macrophage-hTDCs communication was also investigated using the magnetic parameters identified in a previous work. The PEMF influences a macrophage pro-regenerative phenotype and favors the synthesis of anti-inflammatory mediators. These outcomes observed in cell contact co-cultures may be mediated by FAK signaling. The impact of the PEMF overcomes the effect of IL-1β-treated-hTDCs, supporting PEMF immunomodulatory actions on macrophages. This work highlights the relevance of intercellular communication in tendon healing and the beneficial role of the PEMF in guiding inflammatory responses toward regenerative strategies. Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

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18 pages, 4607 KiB

Open AccessArticle

Uremic Toxins and Ciprofloxacin Affect Human Tenocytes In Vitro

by Erman Popowski, Benjamin Kohl, Tobias Schneider, Joachim Jankowski and Gundula Schulze-Tanzil

Int. J. Mol. Sci. 2020, 21(12), 4241; https://doi.org/10.3390/ijms21124241 - 14 Jun 2020

Cited by 3 | Viewed by 3640

Abstract

Tendinopathy is a rare but serious complication of quinolone therapy. Risk factors associated with quinolone-induced tendon disorders include chronic kidney disease accompanied by the accumulation of uremic toxins. Hence, the present study explored the effects of the representative uremic toxins phenylacetic acid (PAA) and quinolinic acid (QA), both alone and in combination with ciprofloxacin (CPX), on human tenocytes in vitro. Tenocytes incubated with uremic toxins +/- CPX were investigated for metabolic activity, vitality, expression of the dominant extracellular tendon matrix (ECM) protein type I collagen, cell-matrix receptor β1-integrin, proinflammatory interleukin (IL)-1β, and the ECM-degrading enzyme matrix metalloproteinase (MMP)-1. CPX, when administered at high concentrations (100 mM), suppressed tenocyte metabolism after 8 h exposure and at therapeutic concentrations after 72 h exposure. PAA reduced tenocyte metabolism only after 72 h exposure to very high doses and when combined with CPX. QA, when administered alone, led to scarcely any cytotoxic effect. Combinations of CPX with PAA or QA did not cause greater cytotoxicity than incubation with CPX alone. Gene expression of the pro-inflammatory cytokine IL-1β was reduced by CPX but up-regulated by PAA and QA. Protein levels of type I collagen decreased in response to high CPX doses, whereas PAA and QA did not affect its synthesis significantly. MMP-1 mRNA levels were increased by CPX. This effect became more pronounced in the form of a synergism following exposure to a combination of CPX and PAA. CPX was more tenotoxic than the uremic toxins PAA and QA, which showed only distinct suppressive effects. Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

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15 pages, 2083 KiB

Open AccessArticle

Changes of Material Elastic Properties during Healing of Ruptured Achilles Tendons Measured with Shear Wave Elastography: A Pilot Study

by Borys Frankewycz, Leopold Henssler, Johannes Weber, Natascha Platz Batista da Silva, Matthias Koch, Ernst Michael Jung, Denitsa Docheva, Volker Alt and Christian G. Pfeifer

Int. J. Mol. Sci. 2020, 21(10), 3427; https://doi.org/10.3390/ijms21103427 - 12 May 2020

Cited by 9 | Viewed by 3119

Abstract

Therapy options for ruptured Achilles tendons need to take into account the right balance of timing, amount and intensity of loading to ensure a sufficient biomechanical resilience of the healing tendon on the one hand, and to enable an adequate tensile stimulus on the other hand. However, biomechanical data of human Achilles tendons after rupture during the separate healing stages are unknown. Shear wave elastography is an ultrasound technique that measures material elastic properties non-invasively, and was proven to have a very good correlation to biomechanical studies. Taking advantage of this technology, 12 patients who suffered from an acute Achilles tendon rupture were acquired and monitored through the course of one year after rupture. Nine of these patients were treated non-operatively and were included for the analysis of biomechanical behaviour. A significant increase of material elastic properties was observed within the first six weeks after trauma (up to 80% of baseline value), where it reached a plateau phase. A second significant increase occurred three to six months after injury. This pilot study suggests a time correlation of biomechanical properties with the biological healing phases of tendon tissue. In the reparative phase, a substantial amount of biomechanical resilience is restored already, but the final stage of biomechanical stability is reached in the maturation phase. These findings can potentially be implemented into treatment and aftercare protocols. Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

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15 pages, 3039 KiB

Open AccessArticle

Increased Collagen Turnover Impairs Tendon Microstructure and Stability in Integrin α2β1-Deficient Mice

by Daniel Kronenberg, Philipp A. Michel, Eva Hochstrat, Ma Wei, Jürgen Brinckmann, Marcus Müller, Andre Frank, Uwe Hansen, Beate Eckes and Richard Stange

Int. J. Mol. Sci. 2020, 21(8), 2835; https://doi.org/10.3390/ijms21082835 - 18 Apr 2020

Cited by 8 | Viewed by 2788

Abstract

Integrins are a family of transmembrane proteins, involved in substrate recognition and cell adhesion in cross-talk with the extra cellular matrix. In this study, we investigated the influence of integrin α2β1 on tendons, another collagen type I-rich tissue of the musculoskeletal system. Morphological, as well as functional, parameters were analyzed in vivo and in vitro, comparing wild-type against integrin α2β1 deficiency. Tenocytes lacking integrin α2β1 produced more collagen in vitro, which is similar to the situation in osseous tissue. Fibril morphology and biomechanical strength proved to be altered, as integrin α2β1 deficiency led to significantly smaller fibrils as well as changes in dynamic E-modulus in vivo. This discrepancy can be explained by a higher collagen turnover: integrin α2β1-deficient cells produced more matrix, and tendons contained more residual C-terminal fragments of type I collagen, as well as an increased matrix metalloproteinase-2 activity. A greatly decreased percentage of non-collagenous proteins may be the cause of changes in fibril diameter regulation and increased the proteolytic degradation of collagen in the integrin-deficient tendons. The results reveal a significant impact of integrin α2β1 on collagen modifications in tendons. Its role in tendon pathologies, like chronic degradation, will be the subject of future investigations. Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

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15 pages, 2573 KiB

Open AccessArticle

Development of a Cartilage Oligomeric Matrix Protein Neo-Epitope Assay for the Detection of Intra-Thecal Tendon Disease

by Roger Smith, Patrik Önnerfjord, Kristin Holmgren, Shacko di Grado and Jayesh Dudhia

Int. J. Mol. Sci. 2020, 21(6), 2155; https://doi.org/10.3390/ijms21062155 - 20 Mar 2020

Cited by 5 | Viewed by 2525

Abstract

The diagnosis of tendon injury relies on clinical signs and diagnostic imaging but imaging is subjective and does not always correlate with clinical signs. A molecular marker would potentially offer a sensitive and specific diagnostic tool that could also provide objective assessment of healing for the comparison of different treatments. Cartilage Oligomeric Matrix Protein (COMP) has been used as a molecular marker for osteoarthritis in humans and horses but assays for the protein in tendon sheath synovial fluids have shown overlap between horses affected by tendinopathy and controls. We hypothesized that quantifying a COMP neoepitope would be more discriminatory of injury. COMP fragments were purified from synovial fluids of horses with intra-thecal tendon injuries and media from equine tendon explants, and mass spectrometry of a consistent and abundant fragment revealed a ~100 kDa COMP fragment with a new N-terminus at the 78th amino-acid (NH₂-TPRVSVRP) located just outside the junctional region of the protein. A competitive inhibition ELISA based on a polyclonal antibody raised to this sequence yielded more than a 10-fold rise in the mean neoepitope levels for tendinopathy cases compared to controls (5.3 ± 1.3 µg/mL (n = 7) versus 58.8 ± 64.3 µg/mL (n = 13); p = 0.002). However, there was some cross-reactivity of the neoepitope polyclonal antiserum with intact COMP, which could be blocked by a peptide spanning the neoepitope. The modified assay demonstrated a lower concentration but a significant > 500-fold average rise with tendon injury (2.5 ± 2.2 ng/mL (n = 6) versus 1029.8 ± 2188.8 ng/ml (n = 14); p = 0.013). This neo-epitope assay therefore offers a potentially useful marker for clinical use. Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

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12 pages, 1218 KiB

Open AccessArticle

Detection of Age-Related Changes in Tendon Molecular Composition by Raman Spectroscopy—Potential for Rapid, Non-Invasive Assessment of Susceptibility to Injury

by Nai-Hao Yin, Anthony W. Parker, Pavel Matousek and Helen L. Birch

Int. J. Mol. Sci. 2020, 21(6), 2150; https://doi.org/10.3390/ijms21062150 - 20 Mar 2020

Cited by 7 | Viewed by 2385

Abstract

The lack of clinical detection tools at the molecular level hinders our progression in preventing age-related tendon pathologies. Raman spectroscopy can rapidly and non-invasively detect tissue molecular compositions and has great potential for in vivo applications. In biological tissues, a highly fluorescent background masks the Raman spectral features and is usually removed during data processing, but including this background could help age differentiation since fluorescence level in tendons increases with age. Therefore, we conducted a stepwise analysis of fluorescence and Raman combined spectra for better understanding of the chemical differences between young and old tendons. Spectra were collected from random locations of vacuum-dried young and old equine tendon samples (superficial digital flexor tendon (SDFT) and deep digital flexor tendon (DDFT), total n = 15) under identical instrumental settings. The fluorescence-Raman spectra showed an increase in old tendons as expected. Normalising the fluorescence-Raman spectra further indicated a potential change in intra-tendinous fluorophores as tendon ages. After fluorescence removal, the pure Raman spectra demonstrated between-group differences in CH₂ bending (1450 cm⁻¹) and various ring-structure and carbohydrate-associated bands (1000–1100 cm⁻¹), possibly relating to a decline in cellular numbers and an accumulation of advanced glycation end products in old tendons. These results demonstrated that Raman spectroscopy can successfully detect age-related tendon molecular differences. Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

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13 pages, 4966 KiB

Open AccessArticle

Tenogenic Contribution to Skeletal Muscle Regeneration: The Secretome of Scleraxis Overexpressing Mesenchymal Stem Cells Enhances Myogenic Differentiation In Vitro

by Maximilian Strenzke, Paolo Alberton, Attila Aszodi, Denitsa Docheva, Elisabeth Haas, Christian Kammerlander, Wolfgang Böcker and Maximilian Michael Saller

Int. J. Mol. Sci. 2020, 21(6), 1965; https://doi.org/10.3390/ijms21061965 - 13 Mar 2020

Cited by 8 | Viewed by 3247

Abstract

Integrity of the musculoskeletal system is essential for the transfer of muscular contraction force to the associated bones. Tendons and skeletal muscles intertwine, but on a cellular level, the myotendinous junctions (MTJs) display a sharp transition zone with a highly specific molecular adaption. The function of MTJs could go beyond a mere structural role and might include homeostasis of this musculoskeletal tissue compound, thus also being involved in skeletal muscle regeneration. Repair processes recapitulate several developmental mechanisms, and as myotendinous interaction does occur already during development, MTJs could likewise contribute to muscle regeneration. Recent studies identified tendon-related, scleraxis-expressing cells that reside in close proximity to the MTJs and the muscle belly. As the muscle-specific function of these scleraxis positive cells is unknown, we compared the influence of two immortalized mesenchymal stem cell (MSC) lines—differing only by the overexpression of scleraxis—on myoblasts morphology, metabolism, migration, fusion, and alignment. Our results revealed a significant increase in myoblast fusion and metabolic activity when exposed to the secretome derived from scleraxis-overexpressing MSCs. However, we found no significant changes in myoblast migration and myofiber alignment. Further analysis of differentially expressed genes between native MSCs and scleraxis-overexpressing MSCs by RNA sequencing unraveled potential candidate genes, i.e., extracellular matrix (ECM) proteins, transmembrane receptors, or proteases that might enhance myoblast fusion. Our results suggest that musculotendinous interaction is essential for the development and healing of skeletal muscles. Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

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15 pages, 1422 KiB

Open AccessArticle

In Vivo and In Vitro Mechanical Loading of Mouse Achilles Tendons and Tenocytes—A Pilot Study

by Viviane Fleischhacker, Franka Klatte-Schulz, Susann Minkwitz, Aysha Schmock, Maximilian Rummler, Anne Seliger, Bettina M. Willie and Britt Wildemann

Int. J. Mol. Sci. 2020, 21(4), 1313; https://doi.org/10.3390/ijms21041313 - 15 Feb 2020

Cited by 20 | Viewed by 4084

Abstract

Mechanical force is a key factor for the maintenance, adaptation, and function of tendons. Investigating the impact of mechanical loading in tenocytes and tendons might provide important information on in vivo tendon mechanobiology. Therefore, the study aimed at understanding if an in vitro loading set up of tenocytes leads to similar regulations of cell shape and gene expression, as loading of the Achilles tendon in an in vivo mouse model. In vivo: The left tibiae of mice (n = 12) were subject to axial cyclic compressive loading for 3 weeks, and the Achilles tendons were harvested. The right tibiae served as the internal non-loaded control. In vitro: tenocytes were isolated from mice Achilles tendons and were loaded for 4 h or 5 days (n = 6 per group) based on the in vivo protocol. Histology showed significant differences in the cell shape between in vivo and in vitro loading. On the molecular level, quantitative real-time PCR revealed significant differences in the gene expression of collagen type I and III and of the matrix metalloproteinases (MMP). Tendon-associated markers showed a similar expression profile. This study showed that the gene expression of tendon markers was similar, whereas significant changes in the expression of extracellular matrix (ECM) related genes were detected between in vivo and in vitro loading. This first pilot study is important for understanding to which extent in vitro stimulation set-ups of tenocytes can mimic in vivo characteristics. Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

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Review

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16 pages, 732 KiB

Open AccessReview

Molecular and Structural Effects of Percutaneous Interventions in Chronic Achilles Tendinopathy

by Christelle Darrieutort-Laffite, Louis J. Soslowsky and Benoit Le Goff

Int. J. Mol. Sci. 2020, 21(19), 7000; https://doi.org/10.3390/ijms21197000 - 23 Sep 2020

Cited by 13 | Viewed by 3734

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. Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

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21 pages, 1945 KiB

Open AccessReview

Regeneration of Damaged Tendon-Bone Junctions (Entheses)—TAK1 as a Potential Node Factor

by Nina Friese, Mattis Benno Gierschner, Patrik Schadzek, Yvonne Roger and Andrea Hoffmann

Int. J. Mol. Sci. 2020, 21(15), 5177; https://doi.org/10.3390/ijms21155177 - 22 Jul 2020

Cited by 14 | Viewed by 7106

Abstract

Musculoskeletal dysfunctions are highly prevalent due to increasing life expectancy. Consequently, novel solutions to optimize treatment of patients are required. The current major research focus is to develop innovative concepts for single tissues. However, interest is also emerging to generate applications for tissue transitions where highly divergent properties need to work together, as in bone-cartilage or bone-tendon transitions. Finding medical solutions for dysfunctions of such tissue transitions presents an added challenge, both in research and in clinics. This review aims to provide an overview of the anatomical structure of healthy adult entheses and their development during embryogenesis. Subsequently, important scientific progress in restoration of damaged entheses is presented. With respect to enthesis dysfunction, the review further focuses on inflammation. Although molecular, cellular and tissue mechanisms during inflammation are well understood, tissue regeneration in context of inflammation still presents an unmet clinical need and goes along with unresolved biological questions. Furthermore, this review gives particular attention to the potential role of a signaling mediator protein, transforming growth factor beta-activated kinase-1 (TAK1), which is at the node of regenerative and inflammatory signaling and is one example for a less regarded aspect and potential important link between tissue regeneration and inflammation. Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

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25 pages, 2904 KiB

Open AccessReview

EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

by Emmanuelle Havis and Delphine Duprez

Int. J. Mol. Sci. 2020, 21(5), 1664; https://doi.org/10.3390/ijms21051664 - 28 Feb 2020

Cited by 74 | Viewed by 8568

Abstract

Although the transcription factor EGR1 is known as NGF1-A, TIS8, Krox24, zif/268, and ZENK, it still has many fewer names than biological functions. A broad range of signals induce Egr1 gene expression via numerous regulatory elements identified in the Egr1 promoter. EGR1 is also the target of multiple post-translational modifications, which modulate EGR1 transcriptional activity. Despite the myriad regulators of Egr1 transcription and translation, and the numerous biological functions identified for EGR1, the literature reveals a recurring theme of EGR1 transcriptional activity in connective tissues, regulating genes related to the extracellular matrix. Egr1 is expressed in different connective tissues, such as tendon (a dense connective tissue), cartilage and bone (supportive connective tissues), and adipose tissue (a loose connective tissue). Egr1 is involved in the development, homeostasis, and healing processes of these tissues, mainly via the regulation of extracellular matrix. In addition, Egr1 is often involved in the abnormal production of extracellular matrix in fibrotic conditions, and Egr1 deletion is seen as a target for therapeutic strategies to fight fibrotic conditions. This generic EGR1 function in matrix regulation has little-explored implications but is potentially important for tendon repair. Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

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20 pages, 4486 KiB

Open AccessReview

Spectrum of Tendon Pathologies: Triggers, Trails and End-State

by Sara Steinmann, Christian G. Pfeifer, Christoph Brochhausen and Denitsa Docheva

Int. J. Mol. Sci. 2020, 21(3), 844; https://doi.org/10.3390/ijms21030844 - 28 Jan 2020

Cited by 66 | Viewed by 14782

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. Full article

(This article belongs to the Special Issue Achilles Curse and Remedy: Tendon Diseases from Pathophysiology to Novel Therapeutic Approaches)

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