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

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

Cross-talk with exogenous cells: e.g., with macrophages during inflammation by Vinhas et al. [5] and myoblasts at the site of myotendinous junction by Strenzke et al. [6]. 4. Niche chemical composition: e.g., uremic toxins and antibiotics in pathological kidney conditions by Popowski et al. [7]; tissue chemical changes during tendon aging by Yin et al. [8]; and cartilage oligomeric matrix protein (COMP) fragmentation in tendon injury by Smith et al. [9]. 5.
Tendon structural composition and biomechanical properties: e.g., alterations in elastic properties after tendon injury by Frankewycz et al. [10] and in vitro and in vivo response of tenocytes to mechanical stimulation by Fleischhacker et al. [11]. 6.
A total of eight original articles and four review articles are published, as summarized in Table 1. Cross-talk between macrophages and human tendon-derived cells (hTDCs), using co-culture model with and without IL-1β stimulation, was investigated. Furthermore, the potential modulatory effect of pulsed electromagnetic fields (PEMFs) was examined. The PEMFs influenced a macrophage pro-regenerative and anti-inflammatory phenotype, and overcame the effect of IL-1β-treated hTDCs, thus suggesting a beneficial role of the PEMF in guiding inflammatory responses toward tissue regeneration.
In vitro studies Erman Popowski, Benjamin Kohl, Tobias Schneider, Joachim Jankowski, and Gundula Schulze-Tanzil [7] The effects of the uremic toxins phenylacetic acid (PAA) and quinolinic acid (QA), both alone and in combination with ciprofloxacin (CPX), on human tenocytes were studied. CPX, administered at a therapeutic concentration, suppressed tenocyte metabolism. Combinations of CPX with PAA or QA did not cause greater cytotoxicity than incubation with CPX alone. Gene expression of matrix metalloproteinase MMP-1 was increased, while the pro-inflammatory cytokine IL-1β was reduced by CPX, but up-regulated by PAA and QA. Type I collagen protein decreased only in response to high CPX doses, demonstrating that CPX was more tenotoxic than the uremic toxins.
In vitro studies Borys Frankewycz, Leopold Henssler, Johannes Weber, Natascha Platz Batista da Silva, Matthias Koch, Ernst Michael Jung, Denitsa Docheva, Volker Alt, and Christian G. Pfeifer [10] Using shear wave elastography technology, 12 patients who suffered from an acute Achilles tendon rupture were acquired and monitored for one year, revealing a significant increase in tendon scar elastic properties within the first six weeks and a second significant increase three to six months after injury. This pilot study suggested a time correlation of biomechanical properties with the biological healing phases of tendon tissue, which could be implemented in treatment and aftercare protocols. Tendon tissue and cells from wild-type and integrin α2β1 knockout mice were compared. Significantly smaller collagen fibrils, altered dynamic E-modulus, increased C-terminal fragments of type I collagen, and MMP-2 activity were detected in α2β1-deficient tendons. Moreover, the mutant tenocytes produced more collagen in vitro. These results report a significant role of α2β1 in tendon tissue and a potential link to chronic tendinosis.

In vivo and in vitro studies
Roger Smith, Patrik Önnerfjord, Kristin Holmgren, Shacko di Grado, and Jayesh Dudhia [9] Cartilage oligomeric matrix protein (COMP) fragments were purified from synovial fluids of horses with intra-thecal tendon injuries and media from equine tendon explants, and analyzed by mass spectrometry and competitive inhibition ELISA, revealing a significant increase in the COMP neo-epitope with tendon injury, suggesting that this assay could be suitable for clinical use.

In vivo and in vitro studies
Nai-Hao Yin, Anthony W. Parker, Pavel Matousek, and Helen L. Birch [8] In order to gain better understanding of the chemical differences between young and old tendons, fluorescence and Raman combined spectra analyses were carried out with vacuum-dried young and old equine superficial digital flexor and deep digital flexor tendons. The analysis indicated increased fluorescence, changes in intra-tendinous fluorophores, a decline in cellular numbers, and an accumulation of advanced glycation end products as tendons aged, signifying that Raman spectroscopy can successfully detect age-related tendon molecular differences.
In vivo studies To investigate new mechanisms in musculotendinous interaction, myoblasts were exposed to a secretome obtained from a Scleraxis-overexpressing mesenchymal stem cell (MSC) line, which led to a significant increase in myoblast fusion and metabolic activity, but had no effect on myoblast migration and myofiber alignment. RNA sequencing revealed differential expression of genes encoding ECM proteins, transmembrane receptors and proteases between native MSCs and Scleraxis MSCs.
In vitro studies Viviane Fleischhacker, Franka Klatte-Schulz, Susann Minkwitz, Aysha Schmock, Maximilian Rummler, Anne Seliger, Bettina M. Willie, and Britt Wildemann [11] Comparative analysis of in vitro and in vivo cyclic compressive loading of Achilles tendon-derived tenocytes revealed similar expression profiles of tendon-associated gene markers, but interestingly, significant differences in cell shape and gene expression levels of collagen I, collagen III, and MMPs. These data can help in understanding how closely in vitro stimulation of tenocytes mimics the in vivo situation.

Review Articles
Christelle Darrieutort-Laffite, Louis J. Soslowsky, and Benoit Le Goff [12] Various percutaneous treatments have been applied to tendon lesions: e.g., injectable treatments, platelet-rich plasma, corticosteroids, stem cells, MMP inhibitors, and anti-angiogenic agents. This review summarized the molecular and structural effects of such treatments obtained in vitro and in vivo, as well as their efficacy in clinical trials, and concluded that local treatments had some impact on neovascularization, inflammation, or tissue remodeling in animal models, but clinical evidence remained too weak, therefore, further studies are needed to evaluate their value.
Nina Friese, Mattis Benno Gierschner, Patrik Schadzek, Yvonne Roger, and Andrea Hoffmann [3] This review focused on the transition zone from bone to tendon-the enthesis, its anatomical structure, development during embryogenesis, and dysfunction during inflammation, with particular attention on the role of a signaling mediator protein, transforming growth factor beta-activated kinase-1 (TAK1). Furthermore, a short synopsis on the current progress in restorative strategies for damaged enthesis was given.

Emmanuelle Havis and Delphine
Duprez [4] This review provided a broad overview on the roles of the early growth response 1 (EGR1) gene in tendon, cartilage, bone, and adipose tissues, as well as on EGR1 involvement in tissue and organ fibrosis and on the link between its transcriptional activity and abnormal ECM production, suggesting EGR1 as a potential therapeutic target to fight fibrotic conditions or to modulate tendon repair. Sara Steinmann, Christian G. Pfeifer, Christoph Brochhausen, and Denitsa Docheva [1] This review encompassed detailed information on morbidity and clinical relevance of tendinopathies; histopathological, structural, cellular, epigenetic, transcriptomic, proteomic, and metabolomic changes during tendinopathy; involvement of vasculature, inflammation, and neurons; and biochemical and biomechanical alterations, as well as on the current tendinopathy management strategies. A graphical summary on the current knowledge of triggers, trails, and the end state of tendinopathies was provided. The review anticipated a more systematic and multidisciplinary approach to decipher the complexity behind tendinopathy and to outline possible ways forward to combat tendinopathy.
Funding: This research received no external funding.
Acknowledgments: Denitsa Docheva acknowledges the financial support of the EU H2020-WIDESPREAD-05 -2017-Twinning Grant "Achilles: Overcoming specific weakness in tendon biology to design advanced regenerative therapies" Proposal Nr. 810850 and the consortium partners Manuela E. Gomes, Dimitrios Zeugolis and Christopher H. Evans for collaboration.

Conflicts of Interest:
The author declares no conflict of interest.