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Objective: To assess the mechanism of supraspinatus tendinopathy induced by type 2 diabetes mellitus (T2DM) in rats using untargeted metabolomics analysis., Methods: The liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics approach was used to screen tendon biomarkers of supraspinatus tendinopathy in rats with T2DM. Seventy-eight Sprague-Dawley rats were divided into normal group (NG) and T2DM groups. Rats in T2DM groups were divided into 12-week (T2DM-12w), and 24-week (T2DM-24w) subgroups according to the time point of the establishment of the T2DM rat model. Histological evaluation (modified Bonar score) and biomechanical testing were used to analyze the adverse effects of type 2 diabetes on the tendon of the supraspinatus muscle in rats.Three comparable groups were set up, including T2DM-12w group vs. NG, T2DM-24w group vs. NG, and T2DM-24w group vs. T2DM-12w group. Differentially expressed metabolites (DEMs) in the supraspinatus tendons in the three groups of rats were analyzed using LC-MS, and data were analyzed using multivariate statistical methods to screen potential biomarkers. The DEMs included in the intersection of the three groups were identified as those associated with the development of diabetic supraspinatus tendinopathy, and trend analysis and pathway topology analysis were performed., Results: With the progression of diabetes, the tendinopathy of the supracinatus muscle of diabetic rats gradually intensified, mainly manifested as inflammatory reactions, disordered collagen fibers, fat infiltration, and increased modified Bonar score. The intersection of DEMs among the three comparable groups was resulted in the identification of 10 key DEMs, in which melezitose and raffinose showed a continuous increasing trend with the prolongation of disease course. By pathway topology analysis, 10 DEMs (P < 0.01) were mainly associated with the pathways of galactose metabolism, which could be involved in the development of diabetes-induced supraspinatus tendinopathy., Conclusion: T2DM causes tendinopathy of the supraspinatus muscle in rats. 10 key DEMs obtained by untargeted metabolomics assay suggested that the development of diabetes-induced supraspinatus tendinopathy was associated with changes in metabolic pathways, such as galactose metabolism. melezitose and raffinose hold promise as a biomarker for disease discrimination and/or disease indication in diabetic supraspinatus tendinopathy., Competing Interests: Declarations Ethics approval and consent to participate This study was carried out in accordance with NIH guidelines for the care and use of laboratory animals (8th edition, NIH). The study protocol was approved by the Ethics Committee of Experimental Animals of the Affiliated Hospital of Qingdao University (Approval No. 20220505SD8020221210126). All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The methods are reported in accordance with ARRIVE guidelines (https://arriveguidelines.org) for the reporting of animal experiments. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Objective: This study aimed to investigate the association between acromial morphology and the incidence and extent of calcific tendonitis., Methods: Ninety-two patients (33 male, 59 female; mean age: 47 ± 9.7) with calcific tendonitis were included in this retrospective study. Critical shoulder angle (CSA), slope angle, lateral acromial angle (LAA), acromion index (AI), acromial type according to Bigliani, and the morphology of the calcific deposits according to Gartner and Heyer were assessed on x-rays. The localization and volume of the calcific deposits were assessed using magnetic resonance imaging (MRI). Patients were divided into 2 groups: CSA < 33° (group 1) and CSA ≥ 33° (group 2)., Results: The median CSA was 33.5° (range=23°-51°), lateral acromial angle (LAA) was 83.6° (range=60°-106°), acromial index (AI) was 0.7 (range=0.4-0.9), and slope angle was 24.1° (range=3°-40°). Lateral acromial angle (P=.000) and AI (P=.000) were statistically different between the 2 groups. Critical shoulder angle was correlated with LAA (P=.000) and AI (P=.000); deposit volumes were correlated with slope angle (P=.001), Bigliani type of the acromion (P=.009), and deposit stage according to Gartner and Heyer (P=.004). There was a correlation between deposit localization and its volume; the size of the deposit increased anteriorly (P=.000)., Conclusion: This study has shown that CSA failed to quantify a patient's predisposition to calcific tendonitis. However, the findings demonstrate a relationship between the morphological parameters in the sagittal plane, such as acromial slope and deposit volume, which deserve further research., Level of Evidence: Level III, Prognostic Study.

The lack of representative in vitro models recapitulating human tendon (patho)physiology is among the major factors hindering consistent progress in the knowledge-based development of adequate therapies for tendinopathy.Here, an organotypic 3D tendon-on-chip model is designed that allows studying the spatiotemporal dynamics of its cellular and molecular mechanisms.Combining the synergistic effects of a bioactive hydrogel matrix with the biophysical cues of magnetic microfibers directly aligned on the microfluidic chip, it is possible to recreate the anisotropic architecture, cell patterns, and phenotype of tendon intrinsic (core) compartment. When incorporated with vascular-like vessels emulating the interface between its intrinsic-extrinsic compartments, crosstalk with endothelial cells are found to drive stromal tenocytes toward a reparative profile. This platform is further used to study adaptive immune cell responses at the onset of tissue inflammation, focusing on interactions between tendon compartment tenocytes and circulating T cells.The proinflammatory signature resulting from this intra/inter-cellular communication induces the recruitment of T cells into the inflamed core compartment and confirms the involvement of this cellular crosstalk in positive feedback loops leading to the amplification of tendon inflammation.Overall, the developed 3D tendon-on-chip provides a powerful new tool enabling mechanistic studies on the pathogenesis of tendinopathy as well as for assessing new therapies., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Tendon stem/progenitor cells (TSPCs) are crucial for tendon repair, regeneration, and homeostasis. Dysfunction of TSPCs, due to aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, contributes to tendinopathy. Unfortunately, the effectiveness of conventional subcutaneous injection targeting at suppressing JAK/STAT signaling pathway is limited due to the passive diffusion of drugs away from the injury site. Herein, a novel poly-gamma-glutamic acid (γ-PGA) dual-barb microneedle (MN) path loaded with TSPCs-derived nanovesicles (NVs) containing JAK/STAT inhibitor WP1066 (MN-WP1066-NVs) for tendinopathy treatment is designed. The dual-barb design of the MN ensures firm adhesion to the skin, allowing for sustained and prolonged release of WP1066-NVs, facilitating enhanced TSPCs self-renewal, migration, and stemness in tendinopathy. In vitro and in vivo experiments demonstrate that the degradation of γ-PGA patch tips facilitates the gradual release of WP1066-NVs at the lesion site. This release alleviates inflammation, suppresses extracellular matrix degradation, and restores normal tendon histological structure by inhibiting the JAK/STAT pathway. These findings suggest that the multifunctional dual-barb MN patch offers a novel and effective therapeutic strategy for tendinopathy treatment., (© 2024 Wiley‐VCH GmbH.)

Achilles tendinopathy is often attributed to overuse, but its pathophysiology remains poorly understood. Disruption to the molecular structure of collagen is fundamental for the onset and progression of tendinopathy but has mostly been investigated in vitro. Here, we interrogated the in vivo molecular structure changes of collagen in rat Achilles tendons following treadmill running. Unexpectedly, the tendons' collagen molecules were not mechanically unfolded by running but denatured through proteolysis during physiological post-run remodeling. We further revealed that running induces inflammatory gene expressions in Achilles tendons and that long-term running causes prolonged, elevated collagen degradation, leading to the accumulation of denatured collagen and tendinopathy development. For applications, we demonstrated magnetic resonance imaging of collagenase-induced Achilles tendon injury in vivo using a denatured collagen targeting contrast agent. Our findings may help close the knowledge gaps in the mechanobiology and pathogenesis of Achilles tendinopathy and initiate new strategies for its imaging-based diagnosis.

Background: The Achilles tendon is one of the thickest, largest, and strongest tendons in the human body. Biomechanically, the AT represents the conjoint tendon of the triceps surae muscle, placed in series with the plantar fascia (PF) to ensure force transmission from the triceps surae toward the toes during walking, running, and jumping. Commonly encountered in the diagnostic evaluation of heel pain, Achilles tendinopathy (AT) refers to a combination of pathological changes affecting the tendon itself often resulting from excessive repetitive stress and overuse. Nevertheless, increasing evidence demonstrates that structural alterations due to overuse or abnormal patterns of skeletal muscle activity are not necessarily restricted to the muscles or tendons but can also affect the fascial tissue. At the same time, there has been recent discussion regarding the role of the fascial tissue as a potential contributor to the pathophysiological mechanisms of the development of several musculoskeletal disorders including tendinopathies. To the best of our knowledge, ultrasound (US) imaging studies on the fascial structures related to the triceps surae complex, as well as their possible correlation with Achillodynia have never been presented in the current literature., Methods: In the present study, a comparative US imaging evaluation of textural features of the suro-Achilleo-plantar complex was performed in 14 healthy controls and 14 symptomatic subjects complaining of midportion AT. The thickness of the Achilles tendon, paratenon, intermuscular fascia, and PF has been assessed with US. In addition, both groups underwent the Victorian Institute of Sport Assessment-Achilles (VISA-A), a disease-specific questionnaire that measures the severity of symptoms of AT. Correlations between quantitative ultrasound measures and VISA-A scores were determined through Pearson or Spearman's rho correlations., Results: Our ultrasonographic findings revealed statistically significant differences (p<0.05) in Achilles tendon and paratenon thicknesses between AT patients and controls. No significant differences were observed between groups in PF at the calcaneal insertion as all mean measures were within the expected range of a normal PF on US imaging. In contrast, in tendinopathic subjects, the deep intermuscular fascia between medial gastrocnemius (MG) and soleus (SOL) muscles is significantly (p<0.01) and considerably thickened compared to those of healthy subjects. Moderate correlations exist between tendon and paratenon thicknesses (r= 0.54, p= 0.04) and between MG-SOL fascia and tendon thicknesses (r= 0.58, p= 0.03). Regarding symptom severity and US morphological findings, the Spearman ρ test showed no correlation., Conclusions: Our data demonstrate that, in symptomatic subjects, US alterations are not restricted to paratenon and intratendinous areas, but also affect upstream structures along the myofascial chain, resulting in thickening of the fascia interposed between MG and SOL muscles. Moreover, positive correlations were found between MG-SOL fascia thickening and abnormalities in AT, paratenon, and symptom severity. Thus, US alterations in the fascial system should be interpreted within the clinical context of patients with AT as they may in turn represent important predictors of subsequent clinical outcomes and could help healthcare professionals and clinicians to refine non-operative treatment strategies and rehabilitation protocols for this disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

The extensor carpi ulnaris (ECU) is primarily responsible for extension and ulnar deviation at the wrist. Secondary to repetitive loading of, or acute trauma to the flexed, supinated and ulnarly deviated wrist, the ECU tendon can be a common source of ulnar-sided wrist pain. Common pathology includes ECU tendinopathy, tenosynovitis, tendon instability, and tendon rupture. Extensor carpi ulnaris pathology commonly occurs in athletes and patients with inflammatory arthritis. Given the multitude of available methods to treat ECU tendon pathology, the aim of our study was to outline operative management of ECU tendon pathology, with emphasis on reviewing techniques for addressing ECU instability. We acknowledge a continuing debate between anatomical and nonanatomical techniques for ECU subsheath reconstruction. However, use of a portion of the extensor retinaculum for nonanatomical reconstruction is commonly used and demonstrates successful outcomes. Future comparative studies on ECU fixation are required to increase data on patient outcomes, to further define and standardize these techniques., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Tendinopathy is one of the most prevalent sports injury diseases in orthopedics. However, there is no effective treatment or medicine. Recently, the discovery of tendon stem cells (TSCs) provides a new perspective to find new therapeutic methods for Tendinopathy. Studies have shown that oxidative stress will inevitably cause TSCs injury during tendinopathy, but the mechanism has not been fully elucidated. Here, we report the oxidative damage of TSCs induced by H 2 O 2 via ferroptosis, as well, treatment with H 2 O 2 raised the proportion of mitochondria engulfed by autophagosomes in TSCs. The suppression of mitophagy by Mdivi-1 significantly attenuates the H 2 O 2 -induced ferroptosis in TSCs. Mechanically, H 2 O 2 actives the cGAS-STING pathway, which can regulate the level of mitophagy. Interfering with cGAS could impair mitophagy and the classical ferroptotic events. In the rat model of tendinopathy, interference of cGAS could relieve tendon injury by inhibiting ferroptosis. Overall, these results provided novel implications to reveal the molecular mechanism of tendinopathy, by which pointed to cGAS as a potential therapeutic target for the treatment of tendinopathy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

A limited understanding of tendon cell biology in healthy and pathological conditions has impeded the development of effective treatments, necessitating in vitro biomimetic models for studying tendon events. We established a dynamic culture using fibrin scaffolds, bioengineered with tendon stem/progenitor cells ( h TSPCs) from healthy or diseased human biopsies and perfused with 20 ng/mL of human transforming growth factor-β1 for 21 days. Both cell types showed long-term viability and upregulated Scleraxis (SCX-A) and Tenomodulin (TNMD) gene expressions, indicating tenogenic activity. However, diseased h TSPCs underexpressed collagen type I and III (COL1A1 and COL3A1) genes and exhibited lower SCX-A and TNMD protein levels, but increased type I collagen production, with a type I/type III collagen ratio > 1.5 by day 14, matching healthy cells. Diseased h TSPCs also showed constant high levels of pro-inflammatory cytokines, such as IL-8 and IL-6. This biomimetic environment is a valuable tool for studying tenogenic and inflammatory events in healthy and diseased tendon cells and identifying new therapeutic targets.

Advanced age is a major risk factor for age-related degenerative tendinopathy. During aging, tendon stem/progenitor cell (TSPC) function declines owing to the transition from a normal quiescent state to a senescent state. Extracellular vesicles (EVs) from young stem cells are reported to possess anti-aging functions. However, it remains unclear whether EVs from young TSPCs (TSPC-EVs) can rejuvenate senescent TSPCs to delay age-related degeneration. Here, this study finds that TSPC-EVs can mitigate the aging phenotypes of senescent TSPCs and maintain their tenogenic capacity. In vitro studies reveal that TSPC-EVs can reinstall autophagy in senescent TSPCs to alleviate cellular senescence, and that the re-establishment of autophagy is mediated by the PI3K/AKT pathway. Mechanistically, this study finds that thrombospondin 1, a negative regulator of the PI3K/AKT pathway, is enriched in TSPC-EVs and can be transported to senescent TSPCs. Moreover, in vivo studies show that the local delivery of TSPC-EVs can rejuvenate senescent TSPCs and promote their tenogenic differentiation, thereby rescuing tendon regeneration in aged rats. Taken together, TSPC-EVs as a novel cell-free approach have promising therapeutic potential for aging-related degenerative tendinopathy., (© 2024 Wiley‐VCH GmbH.)

This study was designed to investigate the accumulation of advanced glycation end-products (AGEs) and the expression of the receptor of AGEs (RAGE) in tendinopathic tissues. In this study, tendinopathic posterior tibial tendons (PTT) were collected from patients (n=6). Redundant autografts of flexor digitorum longus tendon (FDL; n=3) were used for controls. The control and tendinopathic tendon tissues were used for extraction of proteins for western blot and sectioned for histology and immunohistochemistry. Tendinopathy of the PTT was confirmed histologically by the presentation of disorderly organized collagen fibers, high cellularity and increased vascularity. By immunohistochemistry, heterogeneous accumulation of AGEs was detected on the PTT sections and concentrated in areas, where collagen fibers were disorderly and tangled. In the PTT, roundish tenocytes were also AGEs-positive. In contrast, AGEs were diffuse, lightly stained in the FDL. A greater number of tenocytes within the tendinopathic lesions in the PTT were RAGE positive, compared to the tenocytes in the FDL. Western blot confirmed the expression of AGEs and RAGE in both tendinopathic PTT and control FDL but their band densities were not significantly different. The spatial relation of the accumulated AGEs and RAGE- positive tenocytes within the tendinopathic lesions indicates their involvement in the molecular pathology of tendinopathy., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Aims: To identify and highlight pertinent US features that could serve as imaging biomarkers to describe different patient phenotypes, within Great Trochanteric Pain Syndrome (GTPS) clinical diagnosis., Materials and Methods: Using ultrasound we evaluated eighty-eight clinically diagnosed patients with GTPS, for tendon matrix changes and calcium deposits in the gluteus medius (superoposterior and lateral aspects) and in the gluteus minimus. Peritrochanteric examination included fascia lata, trochanteric bursa, cortical irregularities and the presence of enthesophytes. The association of pathological changes with pain and functionality was evaluated using multivariate regression models., Results: Out of the 88 patients, 86 examinations (97.7%) detected gluteus medius tendinopathy, and 54 patients (61.4%) had gluteus minimus tendinopathy in addition. Calcium deposits were present in 97.7% of patients, associated with tenderness (p = 0.009), and most often located in the gluteus medius rather than in the gluteus minimus (p = 0.014); calcifications were associated with tendon thickness (p = 0.042), hypoechogenicity (p = 0.005) and the presence of partial tears (p = 0.030). Bursa swelling occurred in 36 patients (40.9%); multivariate regression models predicted less pain in patients with bursa distension (p = 0.008) and dysfunction in patients with gluteal muscle atrophy (p = 0.001) and loss of fibrillar pattern in the gluteus medius (p = 0.002)., Conclusion: GTPS involves both degenerative calcifying gluteal tendinopathy and alterations in the peritrochanteric space associated with physical function and pain. The severity of GTPS can be assessed using ultrasound imaging biomarkers., (© 2023. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

Tendinopathy is a common age-related disease which causes significant morbidity for both human athletes and performance horses. In the latter, the superficial digital flexor tendon is an excellent model for human tendinopathies because it is a functional homologue of the human Achilles tendon and a primary site of injuries with strong similarities to the human disease. Corticosteroids have been previously used clinically to treat tendinopathic inflammation, but they upregulate the p53-p21 axis with concomitant reductions in cell proliferation and collagen synthesis in human tenocytes. This phenotype is consistent with the induction of cellular senescence in vitro and in vivo and probably represents an important clinical barrier to their effective use. Because of the many differences in senescence mechanisms between species, this study aimed to evaluate these mechanisms after corticosteroid treatment in equine tenocytes. Exposure to clinically reflective levels of dexamethasone for 48 hours drove equine tenocytes into steroid induced senescence (SIS). This was characterised by permanent growth arrest and upregulation of p53, the cyclin dependent kinase inhibitors p21waf and p16ink4a as well as the matrix degrading enzymes MMP1, MMP2 and MMP13. SIS also induced a distinctive equine senescence associated secretory phenotype (eSASP) characterised by enhanced secretion of IL-8 and MCP-1. Preincubation with resveratrol or the potent SIRT1 activator SRT1720 prevented SIS in equine tenocytes, while treatment with the non-SIRT1 activating resveratrol analogue V29 was equally protective against SIS, consistent with a novel, as yet uncharacterised SIRT1-indendent mechanism which has relevance for the development of future preventative and therapeutic strategies., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Heidari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Tendon calcification is a common clinical condition that frequently occurs as a complication after tendon injury and surgery, or as an expression of fibrodysplasia ossificans progressiva. This condition can be referred to by various names in clinical practice and literature, including tendon ossification, tendon mineralization, heterotopic ossification, and calcific tendonitis. The exact pathogenesis of tendon calcification remains uncertain, but current mainstream research suggests that calcification is mostly cell mediated. To further elucidate the pathogenesis of tendon calcification and to better simulate the overall process, selecting appropriate experimental animal models is important. Numerous animal models have been utilized in various clinical studies, each with its own set of advantages and limitations. In this review, we have discussed the advancements made in research on animal models of tendon calcification, with a focus on the selection of experimental animals, the sites of injury in these models, and the methods employed for modeling., (© 2024 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Achilles tendinopathy (TP) is characterized as the third most common disease of the musculoskeletal system, and occurs in three phases. There is currently no evidence of effective treatment for this medical condition. In this study, the modulatory effects of the minimally invasive technique intratissue percutaneous electrolysis (EPI) and combinations of EPI with four nutritional factors included in the diet, hydroxytyrosol (HT), maslinic acid (MA), glycine, and aspartate (AA), on hepatic intermediary metabolism was examined in Wistar rats with induced tendinopathy at various stages of TP. Results obtained showed that induced tendinopathy produced alterations in the liver intermediary metabolisms of the rats. Regarding carbohydrate metabolism, a reduction in the activity of pro-inflammatory enzymes in the later stages of TP was observed following treatment with EPI alone. Among the combined treatments using nutritional factors with EPI, HT+EPI and AA+EPI had the greatest effect on reducing inflammation in the late stages of TP. In terms of lipid metabolism, the HT+EPI and AA+EPI groups showed a decrease in lipogenesis. In protein metabolism, the HT+EPI group more effectively reduced the inflammatory effects of induced TP. Treatment with EPI combined with nutritional factors might help regulate intermediary metabolism in TP disease and reduce the inflammation process.

Both osteoporosis and tendinopathy are widely prevalent disorders, encountered in diverse medical contexts. Whilst each condition has distinct pathophysiological characteristics, they share several risk factors and underlying causes. Notably, oxidative stress emerges as a crucial intersecting factor, playing a pivotal role in the onset and progression of both diseases. This imbalance arises from a dysregulation in generating and neutralising reactive oxygen species (ROS), leading to an abnormal oxidative environment. Elevated levels of ROS can induce multiple cellular disruptions, such as cytotoxicity, apoptosis activation and reduced cell function, contributing to tissue deterioration and weakening the structural integrity of bones and tendons. Antioxidants are substances that can prevent or slow down the oxidation process, including Vitamin C, melatonin, resveratrol, anthocyanins and so on, demonstrating potential in treating these overlapping disorders. This comprehensive review aims to elucidate the complex role of oxidative stress within the interlinked pathways of these comorbid conditions. By integrating contemporary research and empirical findings, our objective is to outline new conceptual models and innovative treatment strategies for effectively managing these prevalent diseases. This review underscores the importance of further in-depth research to validate the efficacy of antioxidants and traditional Chinese medicine in treatment plans, as well as to explore targeted interventions focused on oxidative stress as promising areas for future medical advancements., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Mast cells are immune cells minimally present in normal tendon tissue. The increased abundance of mast cells in tendinopathy biopsies and at the sites of tendon injury suggests an unexplored role of this cell population in overuse tendon injuries. Mast cells are particularly present in tendon biopsies from patients with more chronic symptom duration and a history of intensive mechanical loading. This study, therefore, examined the cross talk between mast cells and human tendon cells in either static or mechanically active conditions in order to explore the potential mechanistic roles of mast cells in overuse tendon injuries. A coculture of isolated human tenocytes and mast cells (HMC-1) combined with Flexcell Tension System for cyclic stretching of tenocytes was used. Additionally, human tenocytes were exposed to agonists and antagonists of substance P (SP) receptors. Mast cell degranulation was assessed by measuring β-hexosaminidase activity. Transwell and cell adhesion assays were used to evaluate mast cell migration and binding to tendon extracellular matrix components (collagen and fibronectin), respectively. Gene expressions were analyzed using real time qRT-PCR. Our results indicate that mechanical stimulation of human tenocytes leads to release of SP which, in turn, activates mast cells through the Mas-related G-protein-coupled receptor X2 (MRGPRX2). The degranulation and migration of mast cells in response to MRGPRX2 activation subsequently cause human tenocytes to increase their expression of inflammatory factors, matrix proteins and matrix metalloproteinase enzymes. These observations may be important in understanding the mechanisms by which tendons become tendinopathic in response to repetitive mechanical stimulation., (© 2024. The Author(s).)

Tendon calcification is a commonly associated with degenerative tendinopathy of the Achilles tendons in dogs. It is characterised by the formation of calcific deposits and is refractory to treatment, often re-forming after surgical removal. Little is known about its pathogenesis and therefore the aims of this study were to develop an in vitro model of canine tendon calcification and use this model to investigate mechanisms driving calcification. Cells from the canine Achilles tendon were cultured with different calcifying media to establish which conditions were best able to induce specific, cell-mediated calcification. Once optimum calcification conditions had been established, the effect of ATP treatment on calcification was assessed. Results revealed that 2 mM di-sodium phosphate combined with 2 mM calcium chloride provided the optimum calcifying conditions, increasing calcium deposition and expression of osteogenic-related genes similar to those observed in tendon calcification in vivo. ATP treatment inhibited calcification in a dose-dependent manner, reducing calcium deposition and increasing cell viability, while osteogenic-related genes were no longer upregulated. In conclusion, the in vitro model of canine tendon calcification developed in this study provides the ability to study mechanisms driving tendon calcification, demonstrating that ATP plays a role in modulating tendon calcification that should be explored further in future studies., (© 2024. The Author(s).)

The effect of interleukin-38 (IL-38), a recently identified member of the IL-1 family with potential applications in various inflammation-related conditions, on ER stress has not been explored. Furthermore, its role in obesity-associated tendinopathy has not been investigated. In this study, human primary tenocytes were treated with palmitate (200 or 400 μM) and palmitate plus IL-38 (0-50 ng/mL) for 24 h. Western blotting was used to assess ER stress and tendinopathogenic markers in tenocytes. Monodansylcadaverine (MDC) staining was used to evaluate autophagosomes. Apoptosis was determined by cell viability assays, caspase 3 activity assays and TUNEL assays. Cell migration was evaluated by a cell scratch assay. Small interfering (si) RNA transfection was used for target gene silencing. Treatment of tenocytes with IL-38 attenuated apoptosis, restored the balance between MMPs and TIMP-1, and alleviated ER stress under palmitate conditions. IL-38 treatment enhanced AMPK phosphorylation and promoted the expression of autophagy markers related to LC3 conversion, p62 degradation, and autophagosome formation in cultured tenocytes. The effects of IL-38 on ER stress, apoptosis, and MMP-9, MMP-13, and TIMP-1 expression in palmitate-treated tenocytes were abrogated by AMPK siRNA or 3-methyladenine (3MA). These results suggest that IL-38 alleviates ER stress through the AMPK/autophagy pathway, thereby reducing apoptosis and preventing extracellular matrix (ECM) degradation in tenocytes under hyperlipidemic conditions. This study provides a promising therapeutic avenue for treating obesity-related tendinopathy using an endogenous compound such as IL-38., Competing Interests: Conflicts of Interest None, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Achilles tendinopathy is a disabling condition that affects more than 50% of runners. Pre-clinical studies in a large animal model of naturally-occurring tendinopathy similar to human Achilles tendinopathy has shown benefits of autologous bone marrow-derived mesenchymal stem cell (MSC) implantation. However, MSCs are advanced therapies medicinal products (ATMPs), with strict regulatory requirements. Guided by the regulator we carried out a first in man study to assess the safety and efficacy of autologous MSC injection in human patients with non-insertional Achilles tendinopathy. Ten patients, mean age 47 with mid-portion Achilles tendon pain and swelling for more than 6 months, underwent autologous cultured cell injections (median 12.2 × 10 6 , range 5-19 × 10 6 cells) into their Achilles tendon. At 24 weeks follow-up, no serious adverse reactions or important medical events were observed. MOXFQ, EQ-5D-5L, and VISA-A scores improved clinically at 12 and 24 weeks. VAS pain improved increasingly at 6, 12 and 24 weeks. MOXFQ Pain and VISA-A Scores improved > 12 points from baseline to 24 weeks in 8 patients. Maximum anteroposterior tendon thickness as measured by greyscale US decreased by mean 0.8 mm at 24 weeks. This phase IIa study demonstrated the safety of autologous MSC injection for non-insertional Achilles tendinopathy and provides proof-of-concept of the technique in patients, all of whom had previously failed conservative treatments for chronic disease and leads the way for a larger randomised controlled trial., (© 2024. The Author(s).)

Current in vitro models poorly represent the healthy or diseased tendon microenvironment, limiting the translation of the findings to clinics. The present work aims to establish a physiologically relevant in vitro tendon platform that mimics biophysical aspects of a healthy and tendinopathic tendon matrix using a decellularized bovine tendon and to characterize tendon cells cultured using this platform. Bovine tendons were subjected to various decellularization techniques, with the efficacy of decellularization determined histologically. The biomechanical and architectural properties of the decellularized tendons were characterized using an atomic force microscope. Tendinopathy-mimicking matrices were prepared by treating the decellularized tendons with collagenase for 3 h or collagenase-chondroitinase (CC) for 1 h. The tendon tissue collected from healthy and tendinopathic patients was characterized using an atomic force microscope and compared to that of decellularized matrices. Healthy human tendon-derived cells (hTDCs) from the hamstring tendon were cultured on the decellularized matrices for 24 or 48 h, with cell morphology characterized using f-actin staining and gene expression characterized using real-time PCR. Tendon matrices prepared by freeze-thawing and 48 h nuclease treatment were fully decellularized, and the aligned structure and tendon stiffness (1.46 MPa) were maintained. Collagenase treatment prepared matrices with a disorganized architecture and reduced stiffness (0.75 MPa), mimicking chronic tendinopathy. Treatment with CC prepared matrices with a disorganized architecture without altering stiffness, mimicking early tendinopathy (1.52 MPa). hTDCs on a healthy tendon matrix were elongated, and the scleraxis ( SCX ) expression was maintained. On tendinopathic matrices, hTDCs had altered morphological characteristics and lower SCX expression. The expression of genes related to actin polymerization, matrix degradation and remodeling, and immune cell invasion were higher in hTDCs on tendinopathic matrices. Overall, the present study developed a physiological in vitro system to mimic healthy tendons and early and late tendinopathy, and it can be used to better understand tendon cell characteristics in healthy and diseased states.

The objective of the study was to obtain adjusted ultrasonographic reference values of the Achilles tendon thickness (maximum anterior-posterior distance) in adults without (previous) Achilles tendinopathy (AT) and to compare these reference values with AT patients. Six hundred participants were consecutively included, comprising 500 asymptomatic individuals and 100 patients with clinically diagnosed chronic AT. The maximum tendon thickness was assessed using Ultrasound Tissue Characterization. A multiple quantile regression model was developed, incorporating covariates (personal characteristics) that were found to have a significant impact on the maximum anterior-posterior distance of the Achilles tendon. A 95% reference interval (RI) was derived (50th, 2.5th-97.5th percentile). In asymptomatic participants median (95% RI) tendon thickness was 4.9 (3.8-6.9) mm for the midportion region and 3.7 (2.8-4.8) mm for the insertional region. Age, height, body mass index, and sex had a significant correlation with maximum tendon thickness. Median tendon thickness for the midportion region was calculated with the normative equation -2.1 + AGE × 0.021 + HEIGHT × 0.032+ BMI × 0.028 + SEX × 0.05. For the insertional region, the normative equation was -0.34 + AGE × 0.010+ HEIGHT × 0.018 + BMI × 0.022 + SEX × -0.05. In the equations, SEX is defined as 0 for males and 1 for females. Mean (95% CI) difference in tendon thickness compared to AT patients was 2.7 mm (2.3-3.2, p < 0.001) for the midportion and 1.4 mm (1.1-1.7, p < 0.001) for the insertional region. Compared to the asymptomatic population 73/100 (73%) AT patients exhibited increased tendon thickening, with values exceeding the 95% RI. This study presents novel reference values for the thickness of midportion and insertional region of the Achilles tendon, which were adjusted for personal characteristics. Our novel web-based openly accessible calculator for determining normative Achilles tendon thickness (www.achillestendontool.com) will be a useful resource in the diagnostic process. Trial registration number: This trial is registered in the Netherlands Trial Register (NL9010)., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Tendinopathy, characterized by inflammatory and degenerative changes, presents challenges in sports and medicine. In addressing the limitations of conservative management, this study focuses on developing tendon grafts using extrusion bioprinting with platelet-rich plasma (PRP)-infused hydrogels loaded with tendon cells. The objective is to understand paracrine interactions initiated by bioprinted tendon grafts in either inflamed or non-inflamed host tissues. PRP was utilized to functionalize methacrylate gelatin (GelMA), incorporating tendon cells for graft bioprinting. Bioinformatic analyses of overexpressed proteins, predictive of functional enrichment, revealed insights into PRP graft behavior in both non-inflamed and inflamed environments. PRP grafts activated inflammatory pathways, including Interleukin 17 (IL-17), neuroinflammation, Interleukin 33 (IL-33), and chemokine signaling. Interleukin 1 beta (IL-1b) in the graft environment triggered p38 mitogen-activated protein kinase (MAPK) signaling, nuclear factor kappa light chain enhancer of activated B cells (NF-kB) canonical pathway, and Vascular Endothelial Growth Factor (VEGF) signaling. Biological enrichment attributed to PRP grafts included cell chemotaxis, collagen turnover, cell migration, and angiogenesis. Acellular PRP grafts differed from nude grafts in promoting vessel length, vessel area, and junction density. Angiogenesis in cellular grafts was enhanced with newly synthesized Interleukin 8 (IL-8) in cooperation with IL-1b. In conclusion, paracrine signaling from PRP grafts, mediated by chemokine activities, influences cell migration, inflammation, and angiogenic status in host tissues. Under inflammatory conditions, newly synthesized IL-8 regulates vascularization in collaboration with PRP.

The aim of this study was to assess the effectiveness of combining sericin with swimming exercise as a treatment for type-I collagenase-induced Achilles tendinopathy (AT) in rats, with a focus on inflammatory cytokines. An experimental AT model was established using type-I collagenase in male Sprague-Dawley rats, categorized into five groups: Group 1 (Control + Saline), Group 2 (AT), Group 3 (AT + exercise), Group 4 (AT + sericin), and Group 5 (AT + sericin + exercise). Intratendinous sericin administration (0.8 g/kg/mL) took place from days 3 to 6, coupled with 30 min daily swimming exercise sessions (5 days/week, 4 weeks). Serum samples were analyzed using ELISA for tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-10 (IL-10), and total antioxidant-oxidant status (TAS-TOS), alongside histopathological and immunohistochemical assessments of Achilles tendon samples. Elevated TNF-α and IL-1β and decreased IL-10 levels were evident in Group 2; Of these, TNF-α and IL-1β were effectively reduced and IL-10 increased across all treatment groups, particularly groups 4 and 5. Serum TAS was notably lower in Group 2 and significantly increased in Group 5 compared to Group 2. Histopathologically, Group 2 displayed severe degeneration, irregular fibers, and round cell nuclei, while Group 5 exhibited decreased degeneration and spindle-shaped fibers. The Bonar score increased in Group 2 and decreased in groups 4 and 5. Collagen type-I alpha-1 (Col1A1) expression was notably lower in Group 2 ( P  = 0.001) and significantly increased in groups 4 and 5 compared to Group 2 ( P  = 0.011 and 0.028, respectively). This study underscores the potential of sericin and swimming exercises in mitigating inflammation and oxidative stress linked to AT pathogenesis, presenting a promising combined therapeutic strategy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

Objective: This study was conducted to compare the differences in clinical impairments between patients with primary and intrinsic secondary adhesive capsulitis and confirm rotator cuff tendon pathology in intrinsic secondary adhesive capsulitis., Design: This study included 130 patients with unilateral adhesive capsulitis in freezing or frozen stages. Clinical impairment was evaluated using visual analog scale score, shoulder passive range of motion, Cyriax stage, and Constant-Murley score. Plain radiography, ultrasonography, single-contrast arthrography, and intravenous gadolinium-enhanced magnetic resonance imaging were performed in all patients., Results: Among 130 patients, 77 patients were diagnosed as primary adhesive capsulitis and 53 patients as intrinsic secondary adhesive capsulitis. Among intrinsic secondary adhesive capsulitis patients, 44 rotator cuff tendon tears, 6 calcific tendinitis, and 3 rotator cuff tendon tears with calcific tendinitis were observed. No significant intergroup difference was observed in all clinical parameters, including shoulder passive range of motion, visual analog scale, Cyriax stage, and Constant-Murley score. The prevalence of subacromial subdeltoid bursitis was significantly higher in intrinsic secondary adhesive capsulitis compared with primary adhesive capsulitis., Conclusions: There was no significant difference in all clinical parameters investigated between patients with primary and intrinsic secondary adhesive capsulitis caused by rotator cuff tendon pathology., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Tendinopathy is one of the most common musculoskeletal diseases, and mechanical overload is considered its primary cause. However, the underlying mechanism through which mechanical overload induces tendinopathy has not been determined. In this study, we identified for the first time that tendon cells can release extracellular mitochondria (ExtraMito) particles, a subtype of medium extracellular particles (mEPs), into the environment through a process regulated by mechanical loading. RNA sequencing systematically revealed that oxygen-related reactions, extracellular particles, and inflammation were present in diseased human tendons, suggesting that these factors play a role in the pathogenesis of tendinopathy. We simulated the disease condition by imposing a 9% strain overload on three-dimensional mouse tendon constructs in our cyclic uniaxial stretching bioreactor. The three-dimensional mouse tendon constructs under normal loading with 6% strain exhibited an extended mitochondrial network, as observed through live-cell confocal laser scanning microscopy. In contrast, mechanical overload led to a fragmented mitochondrial network. Our microscopic and immunoblot results demonstrated that mechanical loading induced tendon cells to release ExtraMito particles. Furthermore, we showed that mEPs released from tendon cells overloaded with a 9% strain (mEP 9% ) induced macrophage chemotaxis and increased the production of proinflammatory cytokines, including IL-6, CXCL1, and IL-18, from macrophages compared to mEP 0% , mEP 3% , and mEP 6% . Partial depletion of the ExtraMito particles from mEP 9% by magnetic-activated cell sorting significantly reduced macrophage chemotaxis. N-acetyl-L-cysteine treatment preserved the mitochondrial network in overloaded tendon cells, diminishing overload-induced macrophage chemotaxis toward mEP 9% . These findings revealed a novel mechanism of tendinopathy; in an overloaded environment, ExtraMito particles convey mechanical response signals from tendon cells to the immune microenvironment, culminating in tendinopathy., (© 2024. The Author(s).)

Rotator cuff repair is usually successful, but retear is not uncommon. It has been previously identified that there is a higher incidence of apoptosis in the edges of the torn supraspinatus tendon. A prospective cohort study was conducted with 28 patients-14 rotator cuff tear patients, 5 instability patients, and 9 Anterior cruciate ligament reconstruction patients to determine whether there was any increase in several genes implicated in apoptosis, including Fas receptor (FasR), Fas ligand, Aifm-1, Bcl-2, Fadd, Bax, and caspase-3. There was a significant expression of Bax (P=0.2) and FasR (P=0.005) in the edges of torn supraspinatus tendons, and in intact subscapularis tendons, there was a significant expression of caspase-3 (P=0.02) compared with samples from the torn supraspinatus tendon (P=0.04). The cytochrome c pathway, with its subsequent activation of caspase-3, as well as the TRAIL-receptor signaling pathway involving FasR have both been implicated. The elevated expression of Bax supported the model that the Bax to Bcl-2 expression ratio represents a cell death switch. The elevated expression of Bax in the intact subscapularis tissue from rotator cuff tear patients also may confirm that tendinopathy is an ongoing molecular process., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Tendinopathies account for 30% of 102 million annual musculoskeletal injuries occurring annually in the United States. Current treatments, like dry needling, induce microdamage to promote healing but produce mixed success rates. Previously, we showed focused ultrasound can noninvasively create microdamage while preserving mechanical properties in ex vivo murine tendons. This present study compared growth factor, histological, and mechanical effects after focused ultrasound or dry needling treatments in an in vivo murine tendon injury model. Partial Achilles tenotomy was performed in 26 rats. One-week postsurgery, tendons were treated with focused ultrasound (1.5 MHz, 1-ms pulses at 10 Hz for 106 s, p +  = 49 MPa, p -  = 19 MPa) or dry needling (30 G needle, 5 fenestrations over 20 s) and survived for 1 additional week. Blood was collected immediately before and after treatment and before euthanasia; plasma was assayed for growth factors. Treated tendons and contralateral controls were harvested for histology or mechanical testing. No differences were found between treatments in release of insulin growth factor 1 and transforming growth factor beta; vascular endothelial growth factor A concentrations were too low for detection. Histologically, focused ultrasound and dry needling tendons displayed localized fibroblast infiltration without collagen proliferation with no detectable differences between treatments. Mechanically, stiffness and percent relaxation of dry needling tendons were lower than controls (p = 0.0041, p = 0.0441, respectively), whereas stiffness and percent relaxation of focused ultrasound tendons were not different from controls. These results suggest focused ultrasound should be studied further to determine how this modality can be leveraged as a therapy for tendinopathies., (© 2023 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

The diagnosis and management of Achilles tendon ailments continue to be widely discussed by the scientific community. Also, the nomenclature used to describe the tendinopathic lesion in patients changed over the last decades together with the evolution in the knowledge of the physiopathology of Achilles tendinopathy, and unfortunately, through ignorance and possibly laziness, confusion still abounds. To emerge from these foggy paths, some clarifications are still necessary. The present Editorial tries to clarify some of these issues., (© 2024. The Author(s).)

Tendinopathy is a condition characterized by chronic, complex, and multidimensional pathological changes in the tendons. The etiology of tendinopathy is the combination of several factors, and diabetes mellitus (DM) is a risk factor. Increasing evidence has shown that the diabetic microenvironment plays an important role in tendinopathy. However, the mechanism causing tendinopathy in patients with DM remains unclear. Our study found that ferroptosis played an important role in tendinopathy in patients with DM. In vitro, high glucose and high fat treatment was used to simulate the DM microenvironment. Results showed that such a mechanism significantly increased ferroptosis, which was characterized by mass cell death, lipid peroxide accumulation, mitochondrial morphological changes, mitochondrial membrane potential decline, iron overload, and the activation of ferroptosis-related genes, in tendon-derived stem cells cultured in vitro. In the animal studies, db/db mice were used in the DM model, and the db mice had severe tendon injury and high ACSL4 and TfR1 expressions. These phenomena could be alleviated by the ferroptosis inhibitor ferrostatin-1. In conclusion, ferroptosis is associated with tendinopathy in patients with DM, and ferroptosis targeting may be a novel approach for treating diabetic tendinopathy. Our results can provide a new strategy for managing tendinopathy clinically in patients with DM., (© 2023 International Union of Biochemistry and Molecular Biology.)

Low-level Laser Therapy (LLLT) was widely used in clinical practice for tendon disorders. However, the underlying mechanisms and effectiveness of LLLT in treating tendon injury remain unclear. Therefore, the present study was conducted aiming to summarize the evidence regarding the histological, physiological, and biomechanical effects of LLLT on tendon healing in animal and human models. Four databases were searched for relevant literature. Four independent reviewers screened abstracts and full-text articles, extracted relevant data, evaluated the risk of bias, and quantified the quality of evidence. Database searches yielded 1400 non-duplicated citations. Fifty-five studies were included (50 animal and five human studies). Animal studies revealed that LT had stimulating effects on collagen organization, collagen I and collagen II formation, matrix metalloproteinase (MMP)-8, transforming growth factor β1, vascular endothelial growth factor, hydroxyproline, maximum load, maximum elongation before breaking, and tendon stiffness. However, LLLT had inhibitory effects on the number of inflammatory cells, histological scores, relative amount of collagen III, cyclooxygenase-2, prostaglandin E2 (PGE2), interleukin-6, tumor necrosis factor-α, MMP-1, and MMP-3. Although one human study found that LLLT reduced the concentration of PGE2 in peritendinous tissue of the Achilles tendon, other human studies revealed that the effects of LLLT on the physiology and biomechanics of human tendons remained uncertain. LLLT facilitates tendon healing through various histological, physiological, and biomechanical effects in animal models. Only post-LLLT anti-inflammatory effects were found in human studies., (© 2023. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Background: Acute calcific tendinitis (ACT) of the longus colli muscle (LCM) is an inflammatory response due to deposition of calcium hydroxyapatite crystals. It is typically correlated with whiplash and overuse injuries. A common presentation of this inflammatory response is acute but progressive neck pain. It is a rare but important cause of neck pain that should be considered on a differential diagnosis when distinguishing between life-threatening conditions and non-life-threatening causes of neck pain., Case Report: A 51-year-old woman presented to the emergency department (ED) reporting a mild sore throat that progressed to acute neck pain and stiffness. She also reported fatigue, fever, myalgias, and nausea. In the ED, the patient was tachycardic, hypertensive, and mildly febrile with normal oxygen saturation. Examination revealed meningismus and was negative for lymphadenopathy, oropharyngeal findings, and neurologic deficits. Laboratory studies were significant for leukocytosis. Computed tomography (CT) neck was obtained and was notable for calcification of the superior left longus colli muscle with prevertebral and retropharyngeal space edema along the muscle body. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ACT of the LCM is a benign, self-limited condition that can present with features overlapping emergent causes of acute neck pain. Correct diagnosis relies on characteristic radiographic findings on CT. Fortunately, patients may be discharged home with a short course of anti-inflammatories and corticosteroids with near-complete resolution of symptoms. Emergency physicians, therefore, can rule out life-threatening causes of neck pain, while also making a definitive diagnosis and initiating effective management for this pathology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Tendinopathy is a prevalent condition in young athletes and in older nonathletic people. Recent tendinopathy research has shown a growing interest in the role played by genetic factors, basically genes involved in collagen synthesis and regulation, in view of collagen disorganization typically present in tendon pathologies., Design: A case-control, genotype-phenotype association study., Setting: La Ribera Hospital, Valencia, Spain., Participants: A group of 137 young athletes (49 with rotator cuff tendon pathology and 88 healthy counterparts) who played upper-limb-loading sports were clinically and ultrasound (US) assessed for rotator cuff tendinopathy were included., Intervention: Genetic analysis was performed to determine whether there was a relationship between rotator cuff pathology and the genotype., Main Outcome Measures: We hypothesized that the following single nucleotide polymorphisms: COL5a1 rs12722, COL11a1 rs3753841, COL11a1 rs1676486, and COL11a2 rs1799907 would be associated with rotator cuff tendinopathy., Results: A direct relationship between CC genotype and bilateral US pathological images was statistically significant (χ 2 = 0.0051) and confirmed by the Fisher test, with a correlation coefficient of 0.345 and a Cramer's v of 0.26., Conclusion: A significant association was found between COL5a1 rs12722 genotype and rotator cuff pathology, with the CC genotype conferring increased risk of tendon abnormalities and being associated with rotator cuff pathology., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Identify chronic shoulder MRI findings in patients with known shoulder injury related to vaccine administration (SIRVA)., Materials and Methods: Two fellowship-trained musculoskeletal radiologists retrospectively reviewed the MRI of nine patients with clinically established SIRVA. MRI was performed at least 4 weeks after vaccination and included intravenous contrast-enhanced sequences. MRI was reviewed for the presence of erosions, tendonitis, capsulitis, synovitis, bone marrow oedema, joint effusion, bursitis, cartilage defects, rotator cuff lesions, and lymphadenopathy. The number and location of focal lesions were recorded., Results: Erosions of the greater tuberosity were present in 8/9 (89%), tendonitis of the infraspinatus muscle tendon in 7/9 (78%), capsulitis, synovitis, and bone marrow oedema in 5/9 (56%) cases, respectively. Effusion was found in three, and subdeltoid bursitis, rotator cuff lesions as well as cartilage defects in one patient, respectively. None of our included subjects showed axillary lymphadenopathy., Conclusion: In this case series, greater humeral tuberosity erosions, infraspinatus muscle tendonitis, capsulitis, synovitis, and bone marrow oedema were common MRI findings in chronic SIRVA., (© 2023. The Author(s).)

Competing Interests: Competing interests: None declared.

To conduct a systematic review of studies reporting the treatment of tendon injury using biomaterials in animal models. A systematic search was conducted to retrieve studies involving animal models of tendon repair using biomaterials, in PubMed (database construction to August 2022) and Ovid-Embase (1946 to August 2022). Data related to tendon repair with biomaterials were extracted by two researchers, respectively. Risk of bias was assessed following the Cochrane Handbook for Systematic Reviews of Interventions. A statistical analysis was performed based on the classification of tendon repair biomaterials included in our study. A total of 8413 articles were retrieved, with 78 studies included in our analysis. For tendon repair in animal models using biomaterials, the most commonly seen characteristics were as follows: naturally derived biomaterials, rabbits and rats as animal models, surgery as the injury model, and the Achilles tendon as the injury site. The histology and biomechanical recovery of tendon injury following repair are affected by different biomaterials. Studies of tendon repair in animal models indicate that biomaterials can significantly improve repair outcomes, including tendon structure and biomechanics. Among effective biomaterial strategies are the use of new composites and incorporation of cells or growth factors into the material, both of which provide obvious benefits for tendon healing. More high-quality preclinical studies are required to encourage the translation of biomaterials into clinical practice for tendon repair.

Despite the high prevalence of tendon pathology in athletes, the underlying pathogenesis is still poorly understood. Various aetiological theories have been presented and rejected in the past, but the tendon cell response model still holds true. This model describes how the tendon cell is the key regulator of the extracellular matrix and how pathology is induced by a failed adaptation to a disturbance of tissue homeostasis. Such failure has been attributed to various kinds of stressors (eg, mechanical, thermal and ischaemic), but crucial elements seem to be missing to fully understand the pathogenesis. Importantly, a disturbance of tissue pressure homeostasis has not yet been considered a possible factor, despite it being associated with numerous pathologies. Therefore, we conducted an extensive narrative literature review on the possible role of intratendinous pressure in the pathogenesis of tendon pathology. This review explores the current understanding of pressure dynamics and the role of tissue pressure in the pathogenesis of other disorders with structural similarities to tendons. By bridging these insights with known structural changes that occur in tendon pathology, a conceptual model was constituted. This model provides an overview of the possible mechanism of how an increase in intratendinous pressure might be involved in the development and progression of tendon pathology and contribute to tendon pain. In addition, some therapies that could reduce intratendinous pressure and accelerate tendon healing are proposed. Further experimental research is encouraged to investigate our hypotheses and to initiate debate on the relevance of intratendinous pressure in tendon pathology., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tendinopathy describes a complex pathology of the tendon characterized by abnormalities in the microstructure, composition, and cellularity of the tendon, leading to pain, limitation of activity and reduced function. Nevertheless, the mechanism of tendinopathy has not been fully elucidated, and the treatment of tendinopathy remains a challenge. High mobility group box 1 (HMGB1), a highly conserved and multifaceted nuclear protein, exerts multiple roles and high functional variability and is involved in many biological and pathological processes. In recent years, several studies have suggested that HMGB1 is associated with tendinopathy and may play a key role in the pathogenesis of tendinopathy. Therefore, this review summarizes the expression and distribution of HMGB1 in tendinopathy, focuses on the roles of HMGB1 and HMGB1-based potential mechanisms involved in tendinopathy, and finally summarizes the findings on HMGB1-based therapeutic approaches in tendinopathy, probably providing new insight into the mechanism and further potential therapeutic targets of tendinopathy.

Background: Written communication can convey one's emotions, personality, and sentiments. Radiology reports employ medical jargon and serve to document a patients' condition. Patients might misinterpret this medical jargon in a way that increases their anxiety and makes them feel unwell. We were interested whether linguistic tones in MRI reports vary between radiologists and correlate with the severity of pathology., Questions/purposes: (1) Is there variation in linguistic tones among different radiologists reporting MRI results for rotator cuff tendinopathy? (2) Is the retraction of the supraspinatus tendon in millimeters associated with linguistic tones?, Methods: Two hundred twenty consecutive MRI reports of patients with full-thickness rotator cuff defects were collected. Supraspinatus retraction was measured on the MRI using viewer tools. Using Kruskal-Wallis H tests, we measured variation between 11 radiologists for the following tones: positive emotion, negative emotion, analytical thinking, cause, insight, tentativeness, certainty, and informal speech. We also measured the correlation of tones and the degree of tendon retraction. Multilevel mixed-effects linear regression models were constructed, seeking factors associated with the tone, accounting for retraction, the presence of prior imaging, and for the effects of each radiologist (nesting)., Results: There were statistically significant differences for all of the tones by radiologist. In bivariate analysis, greater retraction of the supraspinatus muscle in millimeters was associated with more negative emotion and certainty, and with less tentativeness. In multilevel mixed-effects linear regression, more negative tones were associated with greater retraction and absence of prior imaging. Greater tentativeness was associated with the absence of prior imaging, but not with retraction., Conclusions: Radiology reports have emotional content that is relatively negative, varies by radiologist and is affected by pathology. Strategies for more hopeful, positive, optimistic descriptions of pathology have the potential to help patients feel better without introducing inaccuracies even if unlikely., Level of Evidence: Level III, Diagnostic., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Musculoskeletal tissue degeneration impairs the life quality and motor function of many people, especially seniors and athletes. Tendinopathy is one of the most common diseases associated with musculoskeletal tissue degeneration, representing a major global healthcare burden that affects both athletes and the general population, with the clinical presentation of long-term recurring chronic pain and decreased tolerance to activity. The cellular and molecular mechanisms at the basis of the disease process remain elusive. Here, we use a single-cell and spatial RNA sequencing approach to provide a further understanding of cellular heterogeneity and molecular mechanisms underlying tendinopathy progression., Results: To explore the changes in tendon homeostasis during the tendinopathy process, we built a cell atlas of healthy and diseased human tendons using single-cell RNA sequencing of approximately 35,000 cells and explored the variations of cell subtypes' spatial distributions using spatial RNA sequencing. We identified and localized different tenocyte subpopulations in normal and lesioned tendons, found different differentiation trajectories of tendon stem/progenitor cells in normal/diseased tendons, and revealed the spatial location relationship between stromal cells and diseased tenocytes. We deciphered the progression of tendinopathy at a single-cell level, which is characterized by inflammatory infiltration, followed by chondrogenesis and finally endochondral ossification. We found diseased tissue-specific endothelial cell subsets and macrophages as potential therapeutic targets., Conclusions: This cell atlas provides the molecular foundation for investigating how tendon cell identities, biochemical functions, and interactions contributed to the tendinopathy process. The discoveries revealed the pathogenesis of tendinopathy at single-cell and spatial levels, which is characterized by inflammatory infiltration, followed by chondrogenesis, and finally endochondral ossification. Our results provide new insights into the control of tendinopathy and potential clues to developing novel diagnostic and therapeutic strategies., (© 2023. The Author(s).)

Tendinopathy is a disease with surging prevalence. Lacking understanding of molecular mechanisms impedes the development of therapeutic approaches and agents. Lysine lactylation (Kla) is a newly discovered post-translational modification related to glycolysis. It has long been noted that manipulation of glycolysis metabolism could affect tendon cell function, tendon homeostasis, and healing process of tendon. However, protein lactylation sites in tendinopathy remain unexplored. Here, we conducted the first proteome-wide Kla analysis in tendon samples harvested from patients with rotator cuff tendinopathy (RCT), which identified 872 Kla sites across 284 proteins. Compared with normal counterparts, 136 Kla sites on 77 proteins were identified as upregulated in the pathological tendon, while 56 sites on 32 proteins were downregulated. Function enrichment analysis demonstrated that the majority of proteins with upregulated Kla levels functioned in organization of the tendon matrix and cholesterol metabolism, accompanied by lower expression levels which meant impaired cholesterol metabolism and degeneration of the tendon matrix, indicating potential cross-talk between protein lactylation and expression levels. At last, by western blotting and immunofluorescence, we verified the correlation between high lactylation and the downregulation of matrix and cholesterol-related proteins including BGN, MYL3, TPM3, and APOC3. ProteomeXchange: PXD033146.

Background: Hair follicles are easily accessible and contain stem cells with different developmental origins, including mesenchymal stem cells (MSCs), that consequently reveal the potential of human hair follicle (hHF)-derived MSCs in repair and regeneration. However, the role of hHF-MSCs in Achilles tendinopathy (AT) remains unclear. The present study investigated the effects of hHF-MSCs on Achilles tendon repair in rabbits., Methods: First, we extracted and characterized hHF-MSCs. Then, a rabbit tendinopathy model was constructed to analyze the ability of hHF-MSCs to promote repair in vivo . Anatomical observation and pathological and biomechanical analyses were performed to determine the effect of hHF-MSCs on AT, and quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical staining were performed to explore the molecular mechanisms through which hHF-MSCs affects AT. Furthermore, statistical analyses were performed using independent sample t test, one-way analysis of variance (ANOVA), and one-way repeated measures multivariate ANOVA as appropriate., Results: Flow cytometry, a trilineage-induced differentiation test, confirmed that hHF-derived stem cells were derived from MSCs. The effect of hHF-MSCs on AT revealed that the Achilles tendon was anatomically healthy, as well as the maximum load carried by the Achilles tendon and hydroxyproline proteomic levels were increased. Moreover, collagen I and III were upregulated in rabbit AT treated with hHF-MSCs (compared with AT group; P  < 0.05). Analysis of the molecular mechanisms revealed that hHF-MSCs promoted collagen fiber regeneration, possibly through Tenascin-C (TNC) upregulation and matrix metalloproteinase (MMP)-9 downregulation., Conclusions: hHF-MSCs can be a treatment modality to promote AT repair in rabbits by upregulating collagen I and III. Further analysis revealed that treatment of AT using hHF-MSCs promoted the regeneration of collagen fiber, possibly because of upregulation of TNC and downregulation of MMP-9, thus suggesting that hHF-MSCs are more promising for AT., (Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Objective: To investigate the progression of rotator cuff tendon pathology across one year in manual wheelchair (MWC) users with spinal cord injury (SCI) and matched able-bodied individuals, and to explore the association between pain, age, and duration of wheelchair use with the progression of rotator cuff pathology. Design: Longitudinal cohort study, 1-year follow-up. Setting: Outpatient clinic at a tertiary medical center. Participants: Twenty-four adult MWC users with SCI (20 men) with an average age (SD) of 37(12) years and 24 age and sex-matched able-bodied individuals. Interventions: Not applicable. Main outcome measure(s): Presence of shoulder pain was collected. Magnetic resonance imaging (MRI) abnormalities of rotator cuff tendons including tendinopathy and tendon tears at baseline and 1-year follow-up visits were graded by a board-certified musculoskeletal radiologist, and three categories of tendon pathology scores including individual tendon scores, unilateral cuff scores, and bilateral cuff scores were calculated for each participant. Results: Fifty-four percent of the MWC users reported shoulder pain at both time points which was significantly higher than able-bodied cohort at baseline (17%, P = 0.012) and year 1 (21%, P = 0.021). Rotator cuff tendon pathology was detected as mainly mild tendinopathies and low-grade partial-thickness tears in both cohorts at both time points but was more common in MWC users. The results for the bilateral cuff scores indicated a significant (P < 0.008) progression of rotator cuff tendon pathology in the MWC users over one year. MRI findings did not change significantly for the able-bodied cohort across time. There was no association of pain, age, or duration of MWC use with progression of rotator cuff pathology in MWC user cohort. Conclusion: MWC users had a higher prevalence of pain than matched able-bodied cohort, but pain was minimal and not function-limiting. Bilateral cuff TOTAL scores showed pathology progression in MWC users, but MRI findings remained stable in the able-bodied cohort. MWC users were 3.4 times more likely to experience pathology progression than the able-bodied cohort.

The calcaneal tendon, the largest and strongest in the human body, is created by the common junction of tendons of the gastrocnemius and soleus muscles. It is not a homogenous structure, being represented by layers in various arrangements. Morphological variability can be seen in the connection between the aponeurosis of the gastrocnemius muscle and the soleus muscle. Some types of plantaris tendon can be associated with a higher possibility of Achilles tendinopathy. Moreover, the presence of accessory structures, such as an accessory soleus muscle or additional gastrocnemius muscle heads may result in symptomatic pathologies. The main aim of this review is to summarize the current state of knowledge regarding the calcaneal tendon. Another aim is to present morphological variations of the calcaneal tendon and their clinical significance. Such information may be useful for clinicians, especially orthopedists, and surgeons. This review also provides an overview of embryological development and morphological variation among fetuses. Materials and methods: review was conducted according to PRISMA guidelines. An electronic search was conducted in five databases. Top quality tools were used to assess the quality of evidence in the studies reviewed. Research papers that made up the database of this review were analyzed, selected and assessed by two independently working researchers., (© 2023. The Author(s).)

Age-related tendon disorder, a primary motor system disease, is characterized by biological changes in the tendon tissue due to senescence and seriously affects the quality of life of the elderly. The pathogenesis of this disease is not well-understood. Tendon stem/progenitor cells (TSPCs) exhibit multi-differentiation capacity. These cells are important cellular components of the tendon because of their roles in tendon tissue homeostasis, remodeling, and repair. Previous studies revealed alterations in the biological characteristics and tenogenic differentiation potential of TSPCs in senescent tendon tissue, in turn contributing to insufficient differentiation of TSPCs into tenocytes. Poor tendon repair can result in age-related tendinopathies. Therefore, targeting of senescent TSPCs may restore the tenogenic differentiation potential of these cells and achieve homeostasis of the tendon tissue to prevent or treat age-related tendinopathy. In this review, we summarize the biological characteristics of TSPCs and histopathological changes in age-related tendinopathy, as well as the potential mechanisms through which TSPCs contribute to senescence. This information may promote further exploration of innovative treatment strategies to rescue TSPCs from senescence., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Thymoquinone is a major bioactive compound present in the black seeds of the Nigella sativa. Tendon injuries are almost 50% of all musculoskeletal injuries. The recovery of tendon after surgery has become a significant challenge in orthopedics., Design: The purpose of this study was to investigate the healing effect of thymoquinone injections in 40 New Zealand rabbits tendon traumatic models., Materials and Methods: Tendinopathy was induced by trauma using surgical forceps on the Achilles tendon. Animals were randomly divided into 4 groups: (1) normal saline injection (control), (2) DMSO injection, (3) thymoquinone 5% w/w injection, and (4) thymoquinone 10% w/w injection. Forty-two days after surgery, biochemical and histopathological evaluations were done, and biomechanical evaluation was conducted 70 days after surgery., Results: Breakpoint and yield points in treatment groups were significantly higher compared to control and DMSO groups. Hydroxyproline content in the 10% thymoquinone receiving group was higher than all groups. Edema and hemorrhage in the histopathological evaluation were significantly lower in the thymoquinone 10% and thymoquinone 5% receiving groups compared to control and DMSO groups. Collagen fibers, collagen fibers with fibrocytes, and collagen fibers with fibroblasts were significantly higher in the thymoquinone 10% and thymoquinone 5% receiving groups compared to control groups., Conclusions: Thymoquinone injection in the tendon in the concentration of 10% w/w is a simple and low-cost healing agent that could enhance mechanical and collagen synthesis in traumatic tendinopathy models in rabbit., (© 2023. The Author(s).)

Coronavirus disease 2019 (COVID-19) vaccines have been widely used and have been shown to be effective in combating the pandemic. However, various side effects have been reported following vaccination. For instance, a condition called 'shoulder injury related to vaccine administration' (SIRVA) is characterized by shoulder pain and limited range of motion after intramuscular injection of a vaccine into the deltoid muscle of the shoulder. Despite an increase in SIRVA cases, the exact incidence of the disease is unclear, and there are a few reports of SIRVA about the COVID-19 vaccine. Here, we report a rare case of an 83-year-old woman who was diagnosed with calcification in her left shoulder 1 year ago and developed calcific tendinitis after receiving an mRNA vaccine for COVID-19 (Pfizer-BioNTech). Radiographs showed calcification of the supraspinatus tendon, and magnetic resonance images showed continuous inflammatory findings from the subdeltoid bursa to the subacromial bursa. We treated the patient with celecoxib and acetaminophen, and she recovered after about 2 months. In order to prevent SIRVA, the presence of shoulder joint disease should be carefully asked during a pre-vaccination assessment. The puncture point should be chosen with the median point of the deltoid muscle or the anterior-posterior axillary line as landmarks because the more cephalad the puncture position, the greater the chance of causing SIRVA., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The most common etiology of shoulder pain in adults is rotator cuff tear. Elastography is an imaging method that can report the strain and elastic modulus of the biological tissue. We think acoustic radiation force impulse (ARFI) elastography can effectively assess rotator cuff tendinopathy., Purpose: This study aimed to investigate the usefulness of ARFI elastography in evaluating supraspinatus tendinopathy., Materials and Methods: We included 44 patients (22 men, 22 women, median age, 47 years; range, 20-69 years) with unilateral supraspinatus tendinopathy diagnosed with magnetic resonance imaging (MRI) in this prospective study. The normal tendons and tendinopathies, including supraspinatus tendinosis, partial-thickness, and full-thickness supraspinatus tears, were evaluated with ultrasound and ARFI elastography. The ARFI elastography values were compared between healthy and tendinopathy groups, and the gender was compared between elastography values of the normal tendons and tendinopathies using the Mann-Whitney U test., Results: The values of ARFI elastography correlated with tendinopathy. (P = 0.001). The gender differed between the elastography values of the normal tendons (P = 0.002) and tendinopathies (P = 0.001)., Conclusion: ARFI elastography is a non-invasive and feasible method for quantitatively assessing supraspinatus tendinopathy. It can be an alternative method to MRI in diagnosing supraspinatus tendinopathy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This study aimed to evaluate the effectiveness of omega-3 supplementation with exercise in a collagenase-induced Achilles tendinopathy (AT) rat model. Experimental groups (healthy control (HC), AT, exercise (Ex), omega-3 (W), and Ex+W) were randomly allocated. After a week of adaptation, oral omega-3 was initiated for 8 weeks (5 days/week). The exercise groups performed treadmill running for 30 min/day (5 days/week, 20 m/min, 8 weeks) following one week of adaptation (10 m/min, 15 min/day). Matrix metalloproteinase-13 (MMP-13), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and total antioxidant-oxidant status (TAS) levels were determined in serum samples. Tendon samples were obtained for biomechanical, histopathological, and immunohistochemical assessments. Ultimate tensile force, yield force, stiffness values, collagen type-I alpha 1 expression, and serum TAS significantly decreased ( P  < 0.05) in AT vs. HC. These values and expression significantly increased in the Ex+W group vs. AT. Serum MMP-13, IL-1β, and TNF-α levels decreased in all treatment groups vs. AT. The most significant decrease was found in the Ex+W group ( P  < 0.01). Histopathologically, the improvement in degeneration was statistically significant in the Ex+W group ( P  < 0.05). Immunohistochemically, MMP-13, IL-1β, TNF-α, and nitric oxide synthase-2 expression was decreased in all treatment groups vs. AT. In conclusion, omega-3 and exercise might be recommended in AT patients.

Aging is a complex and progressive process where the tissues of the body demonstrate a decreased ability to maintain homeostasis. During aging, there are substantial cellular and molecular changes, with a subsequent increase in susceptibility to pathological degeneration of normal tissue function. In tendon, aging results in well characterized alterations in extracellular matrix (ECM) structure and composition. In addition, the cellular environment of aged tendons is altered, including a marked decrease in cell density and metabolic activity, as well as an increase in cellular senescence. Collectively, these degenerative changes make aging a key risk factor for the development of tendinopathies and can increase the frequency of tendon injuries. However, inconsistencies in the extent of age-related degenerative impairments in tendons have been reported, likely due to differences in how "old" and "young" age-groups have been defined, differences between anatomically distinct tendons, and differences between animal models that have been utilized to study the impact of aging on tendon homeostasis. In this review, we address these issues by summarizing data by well-defined age categories (young adults, middle-aged, and aged) and from anatomically distinct tendon types. We then summarize in detail how aging affects tendon mechanics, structure, composition, and the cellular environment based on current data and underscore what is currently not known. Finally, we discuss gaps in the current understanding of tendon aging and propose key avenues for future research that can shed light on the specific mechanisms of tendon pathogenesis due to aging.