Search Results (70)

Background/Objectives: Injuries to the anterior cruciate ligament (ACL) frequently occur in physically active populations and often lead to long-term complications, such as osteoarthritis and recurrent injury. The ACL’s structural integrity depends on extracellular matrix (ECM) remodeling, regulated by matrix metalloproteinases (MMPs). This study examined the association between three polymorphisms—MMP1 rs1799750, MMP10 rs486055, and MMP12 rs2276109—and ACL injury outcomes, including injury frequency, strain, partial rupture, and complete rupture. Methods: A total of 296 physically active, unrelated Caucasian males participated in this case–control study, including 160 with ACL injuries (classified as ACLF—ACL injury frequency, ACLS—strain, ACLRP—partial rupture, ACLRC—complete rupture, and ACL—general ACL injury) and 136 healthy controls (CON) with no previous ACL injuries. All injuries resulted from non-contact mechanisms. Results: The MMP1 rs1799750 polymorphism showed a protective effect against ACL injury compared to controls (OR = 0.42, 95% CI: 0.21–0.85, Padj = 0.014). Within the injury group, MMP10 rs486055 was significantly associated with partial ruptures, especially in heterozygous carriers (OR = 3.47, 95% CI: 1.64–7.33, p = 0.001). The MMP12 rs2276109 variant, under a dominant model, was linked to higher injury frequency (OR = 3.80, 95% CI: 1.69–8.54, p = 0.0009) but showed no association with injury severity. Conclusions: The MMP1 rs1799750 polymorphism showed a protective effect against ACL injury, MMP10 rs486055 was associated with an increased risk of partial rupture, and MMP12 rs2276109 was linked to higher injury frequency. These findings highlight the complex genetic and biomechanical interactions underlying ACL injuries. The MMP1 rs1799750 polymorphism showed a protective effect (58% reduction in the odds compared to controls) against ACL injury, MMP10 rs486055 was associated with an increased risk (3.47 times higher odds) of partial rupture, and MMP12 rs2276109 was linked to 3.8 times higher odds of an injury. Identifying genetic risk factors may support personalized injury prevention and rehabilitation strategies, offering new opportunities to reduce long-term complications in athletes and active individuals. Full article

Background/Objectives: Hypoxic–ischemic encephalopathy (HIE) is a common neurological outcome of perinatal asphyxia, with cerebral palsy (CP) being the most severe lasting effect. Perinatal brain injury activates the immune system and induces the release of inflammatory mediators. Matrix Metalloproteinases (MMPs) play a crucial role in neuroinflammation and neurodegeneration. This study explored the potential link between MMP2 promoter polymorphisms and the development of CP in children with a history of perinatal asphyxia. Methods: We enrolled 212 patients (130 males and 82 females) with documented perinatal asphyxia, who underwent a comprehensive neurological assessment and neuroimaging, including ultrasound and magnetic resonance imaging (MRI). We genotyped the MMP2 promoter polymorphisms rs243866, rs243865, and rs243864 using real-time polymerase chain reaction. Haplotype frequencies were calculated using Haploview software. Results: As expected, patients with HIE are more likely to develop CP (p = 0.000). In a study of 104 patients who developed CP, the frequencies of the A (rs243866), T (rs243865), and G alleles (rs243864) were nearly twice as high compared to those without CP (p = 0.008, p = 0.019, and p = 0.008, respectively). Haplotype analysis supported these findings, showing that the ATG haplotype was significantly more common among patients who developed CP (p = 0.004). Additionally, in patients with MRI-confirmed brain damage, the ATG haplotype was more frequently observed (p = 0.019). Conclusions: The ATG haplotype of the MMP2 promoter may indicate a risk factor for developing cerebral palsy (CP) in patients who experience perinatal asphyxia and could serve as a potential diagnostic predictor of CP. Full article

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for managing inflammation, but they are associated with gastrointestinal and renal toxicity upon long-term use. Selective cyclooxygenase-2 (COX-2) inhibitors, or coxibs, were developed to avoid these adverse effects while maintaining anti-inflammatory efficacy. However, accumulating evidence indicates that coxibs may increase the risk of cardiovascular complications. This review explores the pathophysiological mechanisms underlying adverse cardiovascular effects in patients treated with COX-2 inhibitors. These mechanisms include an imbalance between prothrombotic and antithrombotic factors, an altered endocannabinoid metabolism, and downregulation of PPARδ, contributing to thrombosis. Additionally, COX-2 inhibition disrupts renal prostaglandin synthesis, particularly PGE2 and prostacyclins, reduces EP4 receptor expression in macrophages, promotes chemotaxis, and elevates arterial pressure via increased iNOS, ADMA, and L-NMMA activity. At the molecular level, genetic polymorphisms, matrix metalloproteinases, signaling cross-talk, and direct cardiomyocyte injury are implicated. Collectively, these alterations promote a prothrombotic state, fluid retention, enhanced vasoconstriction, impaired vasodilation, myocardial injury, cell death, and cardiac fibrosis. Despite these risks, coxibs are often prescribed without adequate cardiovascular assessment, particularly in patients with pre-existing cardiovascular risk factors. Greater awareness of these mechanisms is essential to optimize the benefit–risk ratio in clinical decision-making involving selective COX-2 inhibitors. Full article

Interleukin 17 (IL-17) is a crucial mediator at the interface of periodontal dysbiosis and host immunity. This review synthesizes current evidence on IL-17 in periodontitis (PD), its systemic connections, and the role of IL-17 gene variants. Clinical and experimental studies show that IL-17 rises in periodontal disease and is associated with the severity of PD via action on epithelial, stromal and osteoblastic cells to promote chemokine release, neutrophil recruitment, cyclooxygenase 2 and prostaglandin E2 synthesis, RANKL expression, osteoclastogenesis, and matrix metalloproteinase activity. Periodontopathogens Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans pre-activate the local inflammation-maintaining Th17 response. There is converging evidence linking IL-17-centered signaling with rheumatoid arthritis, diabetes mellitus, and psoriasis in favor of a shared inflammatory network in barrier tissues and synovium. Despite these associations, IL-17 biology is contextually determined with mucosal defense and bone homeostatic roles that caution against unidimensional explanations. Evidence on IL-17A and IL-17F polymorphisms is still heterogeneous across populations with modest and variable risk associations with PD. Clinically, IL-17 in gingival crevicular fluid, saliva, or serum is a potential monitoring biomarker when utilized along with conventional indices. Therapeutically, periodontal therapy that reduces microbial burden may inhibit IL-17 function, and IL-17-targeted therapy has to balance potential benefit to inflammation and bone resorption against safety in oral tissues. The following research must utilize harmonized case definitions, standardized sampling, and multiethnic cohorts, and it must include multiomics to be able to differentiate between causal and compensatory IL-17 signals. Full article

Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in connective tissue remodeling. Matrix metalloproteinase 3 (MMP3) belongs to the MMP family and is associated with the pathogenesis of tendinopathy. Moreover, MMP3 gene polymorphisms have been associated with the risk of tendinopathy development. The goal of this study was to investigate whether this gene polymorphisms could also affect the effectiveness of platelet-rich plasma (PRP) tendinopathy treatment. 107 patients (132 elbows) with lateral elbow tendinopathy underwent PRP injection and were followed for two years at specific follow-up weeks (2, 4, 8, 12, 24, 52, 104). The effectiveness of the therapy was assessed based on patient-reported outcome measures (PROMs) values, specifically visual analogue scale (VAS), quick version of the disabilities of the arm, shoulder and hand (QDASH), patient-rated tennis elbow evaluation (PRTEE), and the achievement of minimal clinically important difference (MCID). Three MMP3 single nucleotide polymorphisms (SNPs) (rs520540, rs591058, rs679620) were genotyped using the TaqMan method. All studied polymorphisms were found to present strong linkage disequilibrium and were associated with the effectiveness of therapy on the VAS scale (week 4) and PRTEE (week 104), as well as with MCID achievement (PRTEE week 4); however, these were not strong associations. The studied SNPs also showed an association with the frequency of hand pain before treatment. MMP3 gene polymorphisms are associated with pain experienced before PRP therapy, but do not show a clear association with treatment effectiveness. Full article

Inflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract, characterized by dysregulated inflammatory responses throughout the gastrointestinal tract. It includes two major phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC), which present with varying gastrointestinal and systemic symptoms. The pathophysiology of IBD is multifactorial including genetic predisposition, mucosal and epithelial dysfunction, environmental injury, and both innate and adaptive immune response abnormalities. Several predisposing genetic factors have been associated with IBD explaining the strong hereditary risk for both CD and UC. For example, Caspase Recruitment Domain 9 (CARD9) variant rs10781499 increases risk for IBD, while other variants are specific to either CD or UC. CD is related to loss-of-function mutations in the nucleotide oligomerization domain containing the protein 2 (NOD2) gene and Autophagy-Related 16-like 1 (ATG16L1) gene. UC risk is increased particularly in Chinese populations by the A-1661G polymorphism of the Cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene. This abnormal CTLA-4 interferes with B- and T-cell responses causing predisposition to autoimmune conditions. Previous studies suggested that IBD results from breakdown of the adaptive immune system, primarily of T-cells. However, new evidence suggests that a primary breakdown of the innate immune system in both CD and UC increases susceptibility to invasion by viruses and bacteria, with a compensatory overactivation of the adaptive immune system as a result. When this viral and microbial invasion continues, further damage is incurred, resulting in a downward cycle of further cytokine activation and epithelial damage. Released biomarkers also affect the permeability of the epithelial membrane, including lactoferrin, nitric oxide (NO), myeloperoxidase (MPO) and its activation of hypochlorous acid, matrix metalloproteinases (MMPs), especially MMP-9, omentin-1, and others. Increased macrophage and dendritic cell dysfunction, increased neutrophil activity, increased numbers of innate lymphoid cells, increased T-cells with decreased regulatory T-cells (Tregs), and changes in B-cell populations and immunoglobulin (Ig) functions are all associated with IBD. Finally, treatment of IBD has typically consisted of medical management (e.g., aminosalicylates and corticosteroids) and lifestyle modification, and surgical intervention in extreme cases. New classes of medications with more favorable side effect profiles include anti-integrin antibodies, vedolizumab, etrolizumab, and carotegrast methyl. Additionally, fecal microbiota transplant (FMT) is a newer area of research for treatment of IBD along with TNF-blockers, JAK inhibitors, and S1PR modulators. However, expense and long preparation time have limited the usefulness of FMT. Full article

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by excessive proliferation of one or more myeloid lineages, frequently accompanied by an elevated risk of thrombotic events. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are implicated in numerous inflammatory and vascular pathophysiological processes. In this study, we analyzed the association between selected MMP polymorphisms, rs1799750, rs243865, rs3025058, rs3918242, and rs17576, and thrombotic risk as well as clinical characteristics in patients with MPNs. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Among the polymorphisms analyzed, a statistically significant association was identified between the MMP-9 rs3918242 CT genotype and an increased risk of arterial thrombosis (OR = 4.206, CI 1.337–13.234, p = 0.014). Moreover, rs3918242 CT was associated with thrombotic events (both arterial and venous thrombosis combined), suggesting a potential contributory role in the prothrombotic phenotype observed in MPNs (OR = 3.200, CI 1.110–9.258, p = 0.031). These findings indicate that genetic variation in MMP-9, particularly rs3918242, may serve as a predictive marker for vascular complications in MPN patients. Further studies with larger cohorts are warranted to confirm these associations and to elucidate the molecular mechanisms underlying the contribution of MMP polymorphisms to thrombosis in MPNs. Full article

Objective: The aim of the present study was to investigate the association of polymorphic variants in matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-3 (MMP-3) genes and the occurrence of persistent apical periodontitis (PAP). Methods: DNA samples from 180 individuals were recruited and divided into two groups: Case group, 79 subjects with a history of PAP; control group, 101 healthy subjects. Five single nucleotide polymorphisms (SNPs) were selected for genotyping: rs243865, rs2285053, and rs2287074 in the MMP-2 gene, and rs679620 and rs522616 in the MMP-3 gene. The chi-square test or Exact Fisher (p < 0.05) and Odds Ratio (CI = 95%) were used to compare the frequencies of genotypes and alleles between the two groups. Results: A positive association was found for the MMP-3 rs522616 AG genotype (p = 0.025), the AG + GG genotypes (p = 0.015), and the G allele (p = 0.016) with PAP. Conclusions: The MMP-3 variant rs522616 was associated with PAP. Similar studies are needed analyzing other genes involved in extracellular matrix dynamics under inflammatory conditions to clarify the role of the genetic factors of PAP. Full article

Background: Ovarian carcinoma (OC) is one of the foremost factors in female carcinoma-related fatalities worldwide. Matrix metalloproteinases (MMPs) are key mediators of tissue remodeling and are linked to tumor aggressiveness, yet there is still a lack of information on the link between genetic changes in MMPs-1,3 and the onset and progression of OC in Egyptian women. This study examines the effects of immunoreactive biomolecule variations of MMPs-1,3, as well as the MMP-1 (1607 1G/2G) and MMP-3 (-1171 5A/6A) genetic variants, on OC risk and progression in Egyptian women. Methods: Tissue specimens embedded in paraffin from 100 OC patients and 60 controls were stained using immunohistochemistry to examine expression of MMPs-1,3. MMP levels were quantified using ELISA, and single-nucleotide polymorphisms (SNPs) of MMPs-1,3 were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Results: Increased levels of MMPs-1,3 in OC patients relative to controls, with more of an increase in the late stages (III and IV) than in the early OC stages (I and II). Additionally, the MMP-1 2G/2G and MMP-3 6A/6A genotypes were more prevalent in OC patients than in controls. Ovarian MMPs-1,3 were comparatively elevated in the identified genotypes compared to the 1G/1G and 5A/5A genotypes, respectively. The transcriptional activity of MMPs-1,3 showed strong potential for distinguishing patients with epithelial ovarian carcinoma (EOC) from controls, boasting an area under the curve (AUC) of 0.956 and 0.816, respectively. Sensitivity and specificity were 94.0% and 90.0% for MMP-1 and 80.0% and 73.3% for MMP-3, respectively. Conclusions: The MMP-1 2G/2G and MMP-3 6A/6A genotypes are correlated with elevated MMP-1 and MMP-3 levels and immunohistochemical expression in carcinomatous ovarian tissues, particularly in advanced stages of OC. This indicates that genetic variations of MMPs-1,3 could be valuable diagnostic and prognostic markers for OC in Egyptian women. Our findings may carry clinical relevance for optimizing OC therapeutic effectiveness, contribute to the growing body of knowledge on the role of MMPs, and shed new light on the genetic background of OC. Future studies with larger sample sizes and comprehensive MMP genetic profiling are needed for results validation. Full article

Purpose: This study explored the relationship between matrix metalloproteinase−8 (MMP−8) gene polymorphisms (−799C/T, −381A/G, and +17C/G) and peri-implantitis, examining clinical parameters including the probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP). Methods: This cross-sectional study involved 120 participants categorized into peri-implantitis and healthy implant groups according to the 2018 classification criteria for periodontal and peri-implant diseases. Saliva samples were analyzed for MMP−8 polymorphisms using polymerase chain reaction (PCR) and Sanger sequencing. Statistical analyses were conducted to evaluate genotype- and allele-specific risks and their associations with clinical parameters. Results: Among the 95 samples analyzed, the −799C/T polymorphism was significantly associated with peri-implantitis, with T allele carriers having a higher diagnosis rate (odds ratio: 3.04, p = 0.010). Although T allele carriers exhibited higher mean values for the probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP), these differences were not statistically significant across genotypes. No associations were found between the −381A/G and +17C/G polymorphisms and peri-implantitis clinical parameters. Conclusions: The −799C/T polymorphism, specifically the T allele, is strongly linked to peri-implantitis, indicating its potential as a genetic marker for disease susceptibility. Further research is required to investigate the role of MMP-8 polymorphisms in peri-implant diseases and to advance the development of personalized diagnostic tools. Full article

Pseudoarthrosis—the failure of normal fracture healing—remains a significant orthopedic challenge affecting approximately 10–15% of long bone fractures, and is associated with significant pain, prolonged disability, and repeated surgical interventions. Despite extensive research into the pathophysiological mechanisms of bone healing, diagnostic approaches remain reliant on clinical findings and radiographic evaluations, with little innovation in tools to predict or diagnose non-union. The present review evaluates the current understanding of the genetic and biological basis of pseudoarthrosis and highlights future research directions. Recent studies have highlighted the potential of specific molecules and genetic markers to serve as predictors of unsuccessful fracture healing. Alterations in mesenchymal stromal cell (MSC) function, including diminished osteogenic potential and increased cellular senescence, are central to pseudoarthrosis pathogenesis. Molecular analyses reveal suppressed bone morphogenetic protein (BMP) signaling and elevated levels of its inhibitors, such as Noggin and Gremlin, which impair bone regeneration. Genetic studies have uncovered polymorphisms in BMP, matrix metalloproteinase (MMP), and Wnt signaling pathways, suggesting a genetic predisposition to non-union. Additionally, the biological differences between atrophic and hypertrophic pseudoarthrosis, including variations in vascularity and inflammatory responses, emphasize the need for targeted approaches to management. Emerging biomarkers, such as circulating microRNAs (miRNAs), cytokine profiles, blood-derived MSCs, and other markers (B7-1 and PlGF-1), have the potential to contribute to early detection of at-risk patients and personalized therapeutic approaches. Advancing our understanding of the genetic and biological underpinnings of pseudoarthrosis is essential for the development of innovative diagnostic tools and therapeutic strategies. Full article

The pathogenesis of the central nervous system (CNS) pathology in tick-borne encephalitis (TBE) remains unclear. We attempted to identify mediators of the blood–brain barrier (BBB) disruption in human TBE in paired serum and cerebrospinal fluid (CSF) samples from 100 TBE patients. CSF albumin quotient (Q_alb) was calculated as a measure of BBB impairment. Concentrations of cytokines, cytokine antagonists, adhesion molecules, selectins and matrix metalloproteinases (MMP) were measured with a multiplex bead assay. Single nucleotide polymorphisms (SNP) in genes MIF, TNF, TNFRSF1A, TNFRSF1B, IL-10, TLR3 and TLR4 were studied in patient blood DNA extracts and analyzed for associations with Q_alb and/or cytokine concentrations. The multivariate regression models of Q_alb were built with the soluble mediators as independent variables. The best models obtained included L-selectin, P-selectin, sVCAM, MMP7, MMP8 (or MMP9) and IL-28A as positive and IL-12p70, IL-15, IL-6Rα/IL-6 ratio and TNF-RII/TNFα ratio as negative correlates of Q_alb. The genotype did not associate with Q_alb, but polymorphism rs4149570 (in TNFRSF1A) associated with TNFα and rs1800629 (TNF) with MIF concentration. We confirm the association of the TNFα-dependent response, L-selectin and MMP8/MMP9 with BBB disruption and identify its novel correlates (IL-12, IL-15, IL-28A, MMP7). We detect no genotype associations with BBB function in TBE. Full article

While the pulmonary effects of regular waterpipe smoking (R-WPS) are well-defined, the impact of occasional waterpipe smoking (O-WPS) on the lungs remains less established. This study investigated the pulmonary toxicity and underlying mechanisms of O-WPS versus R-WPS following 6 months of exposure, focusing on histopathology, inflammation in the lung, bronchoalveolar lavage fluid (BALF), and plasma, as well as oxidative stress, genotoxicity, mitochondrial dysfunction, and the expression of mitogen-activated protein kinases (MAPKs) in lung homogenates. Exposure to both O-WPS and R-WPS resulted in significant histological changes, including increased numbers of alveolar macrophages and lymphocytes, as well as interstitial fibrosis. Only R-WPS increased the number of neutrophil polymorphs and plasma cells. R-WPS also significantly increased the chemokines CXCL1, CXCL2, and CCL2 in the lung, BALF, and plasma, while O-WPS increased CXCL1 and CXCL2 in the lung and CXCL1 in the plasma. Both exposure regimens significantly increased lung injury markers, including matrix metalloproteinase-9 and myeloperoxidase. Additionally, R-WPS induced a significant increase in the cytokines IL1β, IL6, and TNFα in the lung, BALF, and plasma, while O-WPS elevated IL1β and IL6 in the lung. Oxidative stress was observed, with increased levels of thiobarbituric acid reactive substances and superoxide dismutase in both the O-WPS and R-WPS groups. Exposure to either O-WPS or R-WPS triggered genotoxicity and altered mitochondrial complex activities. R-WPS exposure also resulted in elevated expression of p-JNK/JNK, p-ERK/ERK, and p-p38/p38, while O-WPS augmented the p-ERK/ERK ratio in the lungs. Taken together, these findings indicate that both O-WPS and R-WPS contribute to lung injury and induce inflammation, oxidative stress, genotoxicity, and mitochondrial dysfunction, with R-WPS having a more pronounced effect. These effects were associated with the activation of MAPKs. Full article

In open-angle glaucoma, the increase in intraocular pressure (IOP) is caused by an increased resistance to aqueous humour outflow in the trabecular meshwork. Since genetic variability of matrix metalloproteinase (MMP) genes may influence extracellular matrix remodelling, we investigated their association with glaucoma risk and/or response to treatment. The retrospective part of the study included patients with primary open-angle glaucoma and ocular hypertension (OHT); in the prospective part of the study, newly diagnosed patients with POAG or OHT were randomised to receive either latanoprost or selective laser trabeculoplasty (SLT) as the initial treatment. The reduction in IOP was measured 6 weeks after treatment. The following MMP single nucleotide polymorphisms were genotyped: MMP2 rs243865, rs243849, and rs7201; MMP3 rs3025058; MMP9 rs17576, rs17577, rs20544, and rs2250889; MMP14 rs1042704, rs1042704, and rs743257. Logistic regression was used to calculate odds ratios to assess the association between MMP polymorphism and risk of POAG or OHT, glaucoma phenotypes and response to treatment. Only carriers of the MMP3 rs3025058 TT genotype had a significantly higher risk of OHT, more advanced glaucoma, and a higher C/D ratio in the additive and dominant models. None of the investigated MMP polymorphisms were associated with response to treatment with latanoprost and SLT in our study population. Full article

Background/Objectives: Tendon structure is predominantly composed of the extracellular matrix (ECM), and genetic variants in non-collagenous ECM components may influence susceptibility to tendinopathy. We investigated the potential influence of single nucleotide polymorphisms (SNPs) in fibrillin-2 (FBN2), tenascin-C (TNC), and matrix metalloproteinase-3 (MMP3) on the tendon regeneration failure phenotype and impact on the susceptibility to tendinopathy in Brazilian high-performance athletes. Methods: This case–control study was conducted with 397 high-performance athletes from different sports modalities (197 tendinopathy cases and 200 controls), and they were analyzed by validated TaqMan^TM SNP genotyping assays of the SNPs FBN2 (rs331079), TNC (rs2104772), and MMP3 (rs591058). Results: Out of the 197 tendinopathy cases, 63% suffered from chronic tendon pain and 22% experienced more than three episodes of disease manifestation. The TNC-rs2104772-A allele was significantly associated with tendinopathy (OR: 1.4; 95% CI: 1.1–1.8), while athletes carrying the MMP3-rs591058-T allele were linked to an increased risk of more episodes of disease manifestation (OR: 1.7; 95% CI: 1.1–2.8). The TNC-MMP3 tendon regeneration failure phenotype (TNC-A/MMP3-T) was associated with an increased risk of tendinopathy (OR: 1.4; 95% CI: 1.1–2.0) and episodes of disease manifestation (OR: 2.0; 95% CI: 1.2–3.5). Athletes with tendinopathy who had the TNC-A/MMP3-T interaction were more prone to experiencing more than three disease exacerbations (OR: 4.3; 95% CI: 1.8–10.5) compared to TNC-A/TNC-C. Conclusions: This study suggests that rs2104772 and rs591058 SNPs could be involved in the tendon regeneration failure phenotype and may influence the molecular mechanism related to the regulation of the tendon ECM during training workload. Full article