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

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: 15 August 2020.

Special Issue Editor

Prof. Dr. Denitsa Docheva
Website
Guest Editor
Laboratory of Experimental Trauma Surgery, Department of Trauma Surgery, University Regensburg Medical Centre, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
Interests: connective tissues; tendons and ligaments; tendon marker genes; tenomodulin; tendon stem/progenitor cells; tenogenic differentiation; tendon aging and degeneration; tendon rupture; tendon healing; tendon tissue engineering; in vitro 2D and 3D models; in vivo models (pre-clinical and transgene animal models); tendon functional outcome analyses

Special Issue Information

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

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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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 (8 papers)

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Research

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Open AccessArticle
Changes of Material Elastic Properties during Healing of Ruptured Achilles Tendons Measured with Shear Wave Elastography: A Pilot Study
Int. J. Mol. Sci. 2020, 21(10), 3427; https://doi.org/10.3390/ijms21103427 - 12 May 2020
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 [...] Read more.
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
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Open AccessArticle
Increased Collagen Turnover Impairs Tendon Microstructure and Stability in Integrin α2β1-Deficient Mice
Int. J. Mol. Sci. 2020, 21(8), 2835; https://doi.org/10.3390/ijms21082835 - 18 Apr 2020
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, [...] Read more.
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
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Open AccessArticle
Development of a Cartilage Oligomeric Matrix Protein Neo-Epitope Assay for the Detection of Intra-Thecal Tendon Disease
Int. J. Mol. Sci. 2020, 21(6), 2155; https://doi.org/10.3390/ijms21062155 - 20 Mar 2020
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 [...] Read more.
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
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Open AccessArticle
Detection of Age-Related Changes in Tendon Molecular Composition by Raman Spectroscopy—Potential for Rapid, Non-Invasive Assessment of Susceptibility to Injury
Int. J. Mol. Sci. 2020, 21(6), 2150; https://doi.org/10.3390/ijms21062150 - 20 Mar 2020
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 [...] Read more.
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
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Open AccessArticle
Tenogenic Contribution to Skeletal Muscle Regeneration: The Secretome of Scleraxis Overexpressing Mesenchymal Stem Cells Enhances Myogenic Differentiation In Vitro
Int. J. Mol. Sci. 2020, 21(6), 1965; https://doi.org/10.3390/ijms21061965 - 13 Mar 2020
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. [...] Read more.
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
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Open AccessArticle
In Vivo and In Vitro Mechanical Loading of Mouse Achilles Tendons and Tenocytes—A Pilot Study
Int. J. Mol. Sci. 2020, 21(4), 1313; https://doi.org/10.3390/ijms21041313 - 15 Feb 2020
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 [...] Read more.
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
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Review

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Open AccessReview
EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues
Int. J. Mol. Sci. 2020, 21(5), 1664; https://doi.org/10.3390/ijms21051664 - 28 Feb 2020
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 [...] Read more.
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
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Open AccessReview
Spectrum of Tendon Pathologies: Triggers, Trails and End-State
Int. J. Mol. Sci. 2020, 21(3), 844; https://doi.org/10.3390/ijms21030844 - 28 Jan 2020
Cited by 2
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 [...] Read more.
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
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Article
Title: Spectrum of tendon pathologies: triggers, trails and end-state
Authors: Sara Steinmann and Denitsa Docheva

Article
Title: Detection of age-related changes in tendon molecular composition by Raman spectroscopy – potential for rapid, non-invasive assessment of susceptibility to injury
Authors: Yin, N.-H.; Parker, A.W.; Matousek, P.; Birch, H.L.

Article
Title: Development of neo-epitope assays for the detection of equine tendon disease
Authors: Smith RKW, Onnerfjord P*, Holmgren K*, Dudhia J

Review
Title: Multifaceted EGR1 transcription factor as a regulator of matrix production in connective tissues
Authors: Emmanuelle Havis and Delphine Duprez

Title: Ultrasound-guided interventions in chronic Achilles tendinopathy: rational basis of therapies, molecular and structural effects, clinical efficacy
Authors: Christelle Darrieutort-Laffite, etc.

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