A prospective study of 100 patients with rotator cuff tendinopathy showed no correlation between subacromial bursitis and the efficacy of ultrasound-guided corticosteroid injection.

OBJECTIVES: The objective of this study was to determine whether the presence of subacromial bursitis in patients with rotator cuff tendinopathy (RCT) was associated with a better outcome after ultrasound (US)-guided subacromial corticosteroid injection. METHODS: A single-center prospective study was performed including patients referred for subacromial injection to manage RCT. At baseline, all patients received an US-guided intra-bursal injection of betamethasone (1 ml). The primary endpoint was reduced pain 3 months (M3) after the procedure: a good responder was defined by a decrease in Visual Analogue Scale pain of more than 30%. Secondary endpoints included functional recovery assessed by the Oxford Shoulder Score (OSS) and clinical success at 6 weeks (W6). We also explored the association between good clinical response and other factors, such as US or X-ray features. RESULTS: One hundred patients were included and 49 presented with subacromial bursitis. At M3, 60% of patients (54/100) were considered good responders. The rate of good responders did not differ between the bursitis and non-bursitis groups (p = 0.6). During follow-up, OSS improved over time whether bursitis was present or not. We did not find any US or X-ray features significantly associated with a favorable clinical outcome. CONCLUSION: The presence of subacromial bursitis did not influence clinical outcomes at 3 months post-subacromial injection in patients suffering from RCT. CLINICAL RELEVANCE STATEMENT: The presence of subacromial bursitis did not influence clinical outcomes at 3 months post-subacromial corticosteroid injection in patients with rotator cuff tendinopathy. For patient management, looking for ultrasonographic signs of bursitis does not appear relevant for the indication of the injection. KEY POINTS: • Ultrasound-guided subacromial corticosteroid injections led to a significant improvement in 60% of patients suffering from rotator cuff tendinopathy. • The presence of subacromial bursitis was not associated with better improvement at 3 months post-injection. • Except for the Minnesota score referring to job satisfaction, we did not find any baseline clinical, X-ray, or ultrasound characteristics associated with a successful outcome.

Analysis of Pathological Factors of Long Head of Biceps Tendinopathy Based on Network Pharmacology.

OBJECTIVES: To investigate the therapeutic effect and mechanism of Danggui Buxue Tang in the treatment of biceps longus tendon lesions, and to preliminarily explore the relevant factors affecting this injury. METHODS: Using network pharmacology analysis methods, the potential mechanism of Danggui Buxue Tang in treating key lesions of the long head of the biceps brachii muscle was studied. RESULTS: Model analysis revealed 44 protein-protein interactions associated with long head binding. The distribution of 19 strongly correlated targets is Pharmaper>SEA>Stitch>Swiss. Further discovery revealed 17 immune system and inflammation related KEGG pathways with P values less than 0.01. The TNF and sphingolipid signaling pathways are associated with inflammation, while the MAPK signaling pathway is associated with immunity. Finally, it was found that the FoxO and HIF-1 signaling pathways are directly associated with long head restraint injury in the biceps brachii muscle. CONCLUSION: Danggui Buxue Tang inhibits related pathways, regulates the immune system, reduces inflammation, and alleviates disease progression. Danggui Buxue Tang can be an effective choice for treating combined lesions of the long head of the biceps brachii muscle.

Anti-Inflammatory and Antioxidant Properties of a New Mixture of Vitamin C, Collagen Peptides, Resveratrol, and Astaxanthin in Tenocytes: Molecular Basis for Future Applications in Tendinopathies.

Tendinopathy is one of the most frequent musculoskeletal disorders characterized by sustained tissue inflammation and oxidative stress, accompanied by extracellular matrix remodeling. Patients suffering from this pathology frequently experience pain, swelling, stiffness, and muscle weakness. Current pharmacological interventions are based on nonsteroidal anti-inflammatory drugs; however, the effectiveness of these strategies remains ambiguous. Accumulating evidence supports that oral supplementation of natural compounds can provide preventive, and possibly curative, effects. Vitamin C (Vit C), collagen peptides (Coll), resveratrol (Res), and astaxanthin (Asx) were reported to be endowed with potential beneficial effects based on their anti-inflammatory and antioxidant activities. Here, we analyzed the efficacy of a novel combination of these compounds (Mix) in counteracting proinflammatory (IL-1ß) and prooxidant (H2O2) stimuli in human tenocytes. We demonstrated that Mix significantly impairs IL-6-induced IL-1ß secretion, NF-κB nuclear translocation, and MMP-2 production; notably, a synergistic effect of Mix over the single compounds could be observed. Moreover, Mix was able to significantly counteract H2O2-triggered ROS production. Together, these results point out that Mix, a novel combination of Vit C, Coll, Resv, and Asx, significantly impairs proinflammatory and prooxidant stimuli in tenocytes, mechanisms that contribute to the onset of tendinopathies.

Topical glyceryl trinitrate (GTN) and eccentric exercises in the treatment of mid-portion achilles tendinopathy (the NEAT trial): a randomised double-blind placebo-controlled trial.

OBJECTIVES: To investigate if daily treatment with glyceryl trinitrate (GTN) ointment, over 24 weeks combined with a 12-week eccentric exercise programme is more effective for chronic mid-portion Achilles tendinopathy than placebo ointment and eccentric exercise. METHODS: This was a single-site randomised double-blind placebo-controlled trial at an acute hospital, Dublin, Ireland. Patients with chronic mid-portion Achilles tendinopathy were randomised to either 24 weeks of daily GTN ointment or placebo ointment. Both groups received an identical 12-week eccentric exercise programme. The primary outcome measure was the Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire at 24 weeks, which measures pain, function and activity. Secondary outcomes included pain severity, self-reported physical function, calf muscle function, pressure pain thresholds and ultrasound changes. Statistical analyses were performed according to intention-to-treat principles. RESULTS: 76 patients (30 women; 46 men, mean age±SD, 45.6±8.2 years) were recruited for the trial. Significant improvements in VISA-A scores occurred in both groups at 6-week, 12-week and 24-week follow-up. The increase was not significantly different between groups, adjusted mean between-group difference from baseline to week 6, -1.33 (95% CI -6.96 to 4.31); week 12, -1.25 (95% CI -8.0 to 5.49) and week 24, -3.8 (95% CI -10.6 to 3.0); negative values favour GTN. There was no significant between-group difference in any of the secondary outcome measures at 6, 12 and 24 weeks. CONCLUSIONS: Adding daily GTN ointment over 24 weeks to a 12-week eccentric exercise programme did not improve pain, function and activity level in patients with chronic mid-portion Achilles tendinopathy when compared with placebo ointment.

Anatomical consideration of ultrasonography-guided intraoral injection for temporal tendinitis.

Temporal tendinitis is characterized by acute inflammation often resulting from mechanical stress, such as repetitive jaw movements associated with jaw opening and closing and teeth clenching. Treatment for temporal tendinitis typically involves the administration of local anesthetic or corticosteroid injections. However, the complex anatomical structure of the coronoid process, to which the temporalis tendon attaches, located deep within the zygomatic arch, poses challenges for accurate injections. In this study, we aimed to establish guidelines for the safe and effective treatment of temporal tendinitis by using intraoral ultrasonography (US) to identify the anatomical structures surrounding the temporalis tendon and coronoid process. US was performed using an intraoral transducer on 58 volunteers without temporomandibular joint disease. The procedure involved placing the transducer below the occlusal plane of the maxillary second molar. Measurements were taken for the horizontal distance from the anterior border of the coronoid process, observed at the midpoint (MP) of the US images, and the depth of the coronoid process and temporalis muscle from the oral mucosa. The anterior border of the coronoid process was visualized on all US images and classified into three observed patterns at the MP: type A (anterior to the MP, 56.2%), type B (at the MP, 16.1%), and type C (posterior to the MP, 27.7%). The temporalis muscle was located at a mean depth of 3.12 ± 0.68 mm from the oral mucosa. The maxillary second molar is an intraoral landmark for visualizing the anterior border of the coronoid process. The new location information obtained using intraoral US could help identify the safest and most effective injection sites for the treatment of temporal tendinitis.

A Novel Tendon Injury Model, Induced by Collagenase Administration Combined with a Thermo-Responsive Hydrogel in Rats, Reproduces the Pathogenesis of Human Degenerative Tendinopathy.

Patellar tendinopathy is a common clinical problem, but its underlying pathophysiology remains poorly understood, primarily due to the absence of a representative experimental model. The most widely used method to generate such a model is collagenase injection, although this method possesses limitations. We developed an optimized rat model of patellar tendinopathy via the ultrasound-guided injection of collagenase mixed with a thermo-responsive Pluronic hydrogel into the patellar tendon of sixty male Wistar rats. All analyses were carried out at 3, 7, 14, 30, and 60 days post-injury. We confirmed that our rat model reproduced the pathophysiology observed in human patients through analyses of ultrasonography, histology, immunofluorescence, and biomechanical parameters. Tendons that were injured by the injection of the collagenase-Pluronic mixture exhibited a significant increase in the cross-sectional area (p < 0.01), a high degree of tissue disorganization and hypercellularity, significantly strong neovascularization (p < 0.01), important changes in the levels of types I and III collagen expression, and the organization and presence of intra-tendinous calcifications. Decreases in the maximum rupture force and stiffness were also observed. These results demonstrate that our model replicates the key features observed in human patellar tendinopathy. Collagenase is evenly distributed, as the Pluronic hydrogel prevents its leakage and thus, damage to surrounding tissues. Therefore, this model is valuable for testing new treatments for patellar tendinopathy.

Tendon injections - upper extremity.

Imaging-guided tendon procedures aim to reduce pain and increase function by controlling inflammation and stimulating healing. Ultrasound is the preferable guiding modality due to its high resolution and real-time demonstration of the tendinous anatomy and needle positioning. The technique includes appropriate patient positioning, which varies depending on the targeted tendon, as well as sterile and proper draping. For most procedures, we prefer the "in-plane" approach, which demonstrates the entire needle as it advances through different tissue layers. Upper limb injections commonly use corticosteroids and anesthetics with different reported short- and long-term results depending on the tendon treated; better results are obtained in the treatment of tenosynovitis (sliding tendons such as trigger finger and De Quervain's tenosynovitis). Shoulder and elbow tendinopathies (anchor tendons) may also benefit from injections containing irritants or healing stimulants such as dextrose (prolotherapy) and platelet-rich plasma or by the stimulation of healing via tendon perforations (fenestration). The hyaluronic acid injection has also been used in the treatment of both tenosynovitis and tendinopathies. For tendons passing through osteofibrous tunnels, an additional release may be performed, and the techniques are discussed in this review. Therefore, this article provides practicing musculoskeletal radiologists and trainees with a comprehensive review of tendon injection musculoskeletal image-guided procedures.

Plasma rich in growth factors versus corticosteroid injections for management of chronic rotator cuff tendinopathy: a prospective double-blind randomized controlled trial with 1 year of follow-up.

BACKGROUND: Rotator cuff tendinopathy (RCT) is a painful and dysfunctional shoulder condition traditionally considered as a degenerative pathology. However, evidence is pointing to immunocompetent cells and activated stromal fibroblasts as the drivers of a nonresolved inflammatory condition in RCT. As potent anti-inflammatory agents, corticosteroid injections have been among the first-line and the most common therapeutic strategies. Recently, another adjuvant therapy to treat musculoskeletal inflammation-driven painful conditions, namely, platelet-rich plasma (PRP), has emerged as safe and effective. The aim of this study was to compare the clinical efficacy of intratendinous injections of plasma rich in growth factors (PRGF) with conventional intratendinous corticosteroid injections on patients with chronic RCT using patient-reported outcome measures. METHODS: A total of 39 patients received PRGF treatment (3 infiltrations, 1 every other week), whereas 40 patients, as a control group, received corticosteroid (3 infiltrations, 1 every other week). Patients were evaluated before treatment and at 3, 6, and 12 months of follow-up using the University of California Los Angeles (UCLA) scale, Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), and Constant test. The primary outcome of the study was a 15% superior improvement of the PRGF group compared with the corticosteroid group in the UCLA scale and QuickDASH test at 6 months of follow-up, considering this difference to be clinically relevant. RESULTS: Both PRGF and corticosteroid groups showed significant clinical improvement in the 3 scores at all time points of the study compared with baseline. However, at 6 and 12 months of follow-up, the PRGF group had 22.1% and 21.2% superior improvement of the UCLA test, 14.3% and 13.5% for QuickDASH, and 16.4% and 20.2% for the Constant-Murley test, respectively, compared to the corticosteroid group. CONCLUSIONS: Three PRGF intratendinous injections every other week in patients with chronic rotator cuff tendinopathy show significantly superior and sustained pain-relieving and functional improvements compared with corticosteroid intratendinous injections assessed by 3 patient-reported outcome scales at 6 and 12 months of follow-up.

Ultrasound-Guided Iliopsoas Bursal Injections for Management of Iliopsoas Bursitis After Total Hip Arthroplasty.

BACKGROUND: Iliopsoas tendonitis can cause persistent pain after total hip arthroplasty (THA). Nonoperative management of iliopsoas tendonitis includes anti-inflammatory drugs and image-guided corticosteroid injections. This study evaluated the efficacy of ultrasound-guided corticosteroid injections (US-CSIs) for iliopsoas tendonitis following THA. METHODS: We retrospectively reviewed 42 patients who received an US-CSI for iliopsoas tendonitis after primary THA between 2009 and 2020 at a single institution. Outcomes including reoperation, groin pain at last follow-up, additional intrabursal injection, and Harris Hip Score (HHS) were evaluated at a minimum of 1 year. Cross-table lateral radiographs (36 patients) or computed tomography scans (6 patients) were reviewed to determine if anterior cup overhang was present, indicating a mechanical etiology of iliopsoas tendonitis. Descriptive statistics and univariate comparison of HHS preinjection and postinjection were performed, with alpha < 0.05. RESULTS: Among the 22 patients who did not have cup overhang, four (18.2%) had persistent groin pain at mean follow-up of 40 months (range, 14-94) after US-CSI. Three patients had a second injection; none had groin pain at most recent follow-up. No patients required acetabular revision. Mean HHS improved from 74 points (range, 52-94 points) to 91 points (range, 76-100 points; P < .001) at last follow-up. Among the 20 patients who had anterior cup overhang, five underwent acetabular revision after only temporary pain relief from injection. Groin pain was resolved in all revised patients at mean follow-up of 43 months (range, 12-60) after revision. Of the remaining 15 patients, five had persistent groin pain at mean follow-up of 35 months (range, 12-83). Mean HHS improved from 69 points (range, 50-96 points) preinjection to 81 (range, 56-98 points; P = .007) at last follow-up. CONCLUSION: Resolution of groin pain was demonstrated in 78.6% of patients in the cohort; however, those who did not have acetabular overhang had higher rates of success. The overall revision rate was 11.9%. US-CSI appears to be safe and effective in the diagnosis and treatment of iliopsoas tendonitis following primary THA. LEVEL OF EVIDENCE: Level IV, Therapeutic Study.

Examining the Potential of Vitamin C Supplementation in Tissue-Engineered Equine Superficial Digital Flexor Tendon Constructs.

Because equine tendinopathies are slow to heal and often recur, therapeutic strategies are being considered that aid tendon repair. Given the success of utilizing vitamin C to promote tenogenesis in other species, we hypothesized that vitamin C supplementation would produce dose-dependent improvements in the tenogenic properties of tendon proper (TP) and peritenon (PERI) cells of the equine superficial digital flexor tendon (SDFT). Equine TP- and PERI-progenitor-cell-seeded fibrin three-dimensional constructs were supplemented with four concentrations of vitamin C. The gene expression profiles of the constructs were assessed with 3'-Tag-Seq and real-time quantitative polymerase chain reaction (RT-qPCR); collagen content and fibril ultrastructure were also analyzed. Moreover, cells were challenged with dexamethasone to determine the levels of cytoprotection afforded by vitamin C. Expression profiling demonstrated that vitamin C had an anti-inflammatory effect on TP and PERI cell constructs. Moreover, vitamin C supplementation mitigated the degenerative pathways seen in tendinopathy and increased collagen content in tendon constructs. When challenged with dexamethasone in two-dimensional culture, vitamin C had a cytoprotective effect for TP cells but not necessarily for PERI cells. Future studies will explore the effects of vitamin C on these cells during inflammation and within the tendon niche in vivo.

Farrerol alleviates collagenase-induced tendinopathy by inhibiting ferroptosis in rats.

Tendinopathy is mainly characterized by local pain, functional limitation and decreased athletic ability, which seriously affects the quality of life of patients and the career of athletes. Farrerol (FA), one of the main active compounds extracted from Rhododendron and plants in the Rhododendron family, has a wide range of pharmacological activities, such as immunomodulatory, anti-inflammatory and antiviral effects. However, the effect of FA on tendinopathy is unclear. Here, we investigated the pharmacological effect and mechanism of FA in tendon injury through collagenase-induced tendinopathy in vivo and RSL3-induced tenocytes injury in vitro. The results showed that FA alleviated the infiltration of inflammatory cells, promoted tenogenesis and improved mechanical properties of the Achilles tendon in rats. In addition, ferroptosis inducer RSL3 inhibits the tenogenesis in vitro and in vivo, which accelerates the progression of tendinopathy. Moreover, FA effectively inhibited iron accumulation and alleviated ferroptosis in the Achilles tendon. Using in vitro experiments, we found that FA antagonized ferroptosis by reducing lipid peroxidation and iron accumulation in tenocytes. Finally, we found that glutathione peroxidase 4 silencing could block the protective effect of FA on ferroptosis of tenocytes. Therefore, the results of this study suggest that FA can relieve collagenase-induced tendinopathy by inhibiting ferroptosis, and reveal that FA may be a potentially effective drug for the treatment of tendinopathy in the future.

Platelet lysate and tendon healing: comparative analysis of autologous frozen-thawed PRP and ketorolac tromethamine in the treatment of patients with rotator cuff tendinopathy.

Platelet-rich blood derivatives are being nowadays increasingly used in the treatment of tendon-related pathologies as a rich source of growth factors. We sought to ascertain if local application of platelet lysate (PL) to augment rotator cuff repair ameliorates patient outcomes compared to ketorolac tromethamine treated group. A total of forty patients, with clinical diagnosis of Rotator Cuff Tendinopathy were randomized to receive sub acromial injections of PL every week for a total of 3 injections and two injection of ketorolac tromethamine once every two weeks. Subjective assessments included VAS, SPADI and shoulder range of motion were assessed at baseline and at 1 and 6 months after injection. Taking both control and PL groups, it was vividly seen that the outcomes were identical at the initial state, as well as the short-term one; whereas, when considering the 6-month period, there is a seemingly remarkable superiority in PL group in all parameters.

The effect of platelet-rich plasma injection on chronic Achilles tendinopathy and acute Achilles tendon rupture.

Several clinical trials exploring the effect of platelet-rich plasma (PRP) on Achilles tendon rupture (ATR) or Achilles tendinopathy (AT) have been published. However, current evidence is limited to small-sized trials. This study aims to evaluate whether PRP improves the outcomes of ATR or AT. PubMed, Web of Science, EMBASE, and Cochrane Library databases were searched to identify randomized controlled trials comparing PRP injection versus placebo for ATR or AT. Eleven studies with 574 patients were included. Quantitative synthesis suggested that compared with placebo, AT patients in PRP group had higher VISA-A score improvement at six-week follow-up (mean difference (MD) = 2.64; 95% CI) = 1.12 to 4.15). However, there was no significant difference between two groups for VISA-A score improvement at three-month follow-up (MD = 0.93; 95% CI = -2.75 to 4.62), or 6-month follow-up (MD = 5.46; 95% CI = -1.19 to 12.11). In ATR patients, quantitative synthesis suggested that no significant difference was seen between PRP and control group at 3-month, 6-month, and 1-year follow-up. In addition, no significant difference was detected between the two groups in improving tendon thickness and pain for AT patients, and no significant difference was seen in improving heel-rise work, maximum heel-rise height, dorsal and plantar flexion, rate of returning to sports activities, and complication for ATR patients. To conclude, no evidence indicates that PRP injection can improve the patient-reported/clinical/functional outcomes of AT or ATR. The increasing times of PRP injection could improve the outcomes, and further clinical randomized controlled trials are expected to be conducted to verify this hypothesis.

Effects of Hypertonic Dextrose Injection (Prolotherapy) in Lateral Elbow Tendinosis: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically review the effectiveness of hypertonic dextrose prolotherapy (DPT) on pain intensity and physical functioning in patients with lateral elbow tendinosis (LET) compared with other active non-surgical treatments. DATA SOURCES: Systematic search of Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Web of Science, PubMed, Dimensions, Global Health, NHS Health Technology Assessment, Allied and Complementary Medicine, and OVID nursing database from inception to June 15, 2021, without language restrictions. STUDY SELECTION: Two reviewers independently identified parallel or crossover randomized controlled trials that evaluated the effectiveness of DPT in LET. The search identified 245 records; data from 8 studies (354 patients) were included. DATA EXTRACTION: Two reviewers independently extracted data and assessed included studies. The Cochrane Risk of Bias 2 tool was used to evaluate risk of bias. The Grading of Recommendation Assessment, Development, and Evaluation approach was used to assess quality of the evidence. DATA SYNTHESIS: Pooled results favored the use of DPT in reducing tennis elbow pain intensity compared with active controls at 12 weeks postenrollment, with a standardized mean difference of -0.44 (95% confidence interval, -0.88 to -0.01, P=.04) and of moderate heterogeneity (I2=49%). Pooled results also favored the use of DPT on physical functioning compared with active controls at 12 weeks, with Disabilities of the Arm, Shoulder and Hand scores achieving a mean difference of -15.04 (95% confidence interval, -20.25 to -9.82, P<.001) and of low heterogeneity (I2=0.0%). No major related adverse events have been reported. CONCLUSIONS: DPT is superior to active controls at 12 weeks for decreasing pain intensity and functioning by margins that meet criteria for clinical relevance in the treatment of LET. Although existing studies are too small to assess rare adverse events, for patients with LET, especially those refractory to first-line treatments, DPT can be considered a nonsurgical treatment option in carefully selected patients. Further high-quality trials with comparison with other injection therapies are needed.

Effect of Hypertonic Dextrose Injection on Pain and Shoulder Disability in Patients with Chronic Supraspinatus Tendinosis: A Randomized Double-Blind Controlled Study.

OBJECTIVES: To investigate the effect of hypertonic dextrose injection on pain and disability in patients with chronic supraspinatus tendinosis. The secondary aim was to evaluate its effect on the tendon range of motion (ROM) and morphology. DESIGN: Randomized double-blind placebo-controlled trial. SETTING: Outpatient clinic. PARTICIPANTS: Individuals (N=57) with symptomatic chronic supraspinatus tendinosis. INTERVENTIONS: Participants were randomly administered ultrasound-guided injections of 20% hypertonic dextrose (study group, n=29) or 5% normal saline (control group, n=28). MAIN OUTCOME MEASURES: The primary outcome measure was visual analog scale (VAS) scores for pain and Shoulder Pain and Disability Index (SPADI) scores. Secondary outcomes included the ROM and ultrasound examination findings of the supraspinatus tendon at baseline and at 2, 6, and 12 weeks postintervention. RESULTS: The study group exhibited significant improvements in the VAS (mean difference [MD], -2.1; 95% confidence interval [CI], -2.7 to -1.4; P<.001) and SPADI (MD, -11.6; 95% CI, -16.5 to -6.7; P<.001) scores compared with baseline scores at week 2. However, the effect was not sustained to week 6. Flexion ROM increased at weeks 2 (MD, 14.1; 95% CI, 5.7-22.5; P<.001) and 6 (MD, 8.9; 95% CI, 2.4-15.4; P=.003) compared with baseline. The thickness of the supraspinatus tendon improved at weeks 6 (MD, .50; 95% CI, .26-.74; P<.001) and 12 (MD, .61; 95% CI, .37-.84; P<.001) compared with baseline. The ratio of histograms also improved at weeks 6 (MD, .19; 95% CI, .06-.32; P=.002) and 12 (MD, .26; 95% CI, .10-.41; P<.001) compared with baseline. CONCLUSION: Hypertonic dextrose injection could provide short-term pain and disability relief in patients with chronic supraspinatus tendinosis. Ultrasound imaging at week 6 revealed changed tendon morphology.

Antioxidant effect of nicotinamide mononucleotide in tendinopathy.

BACKGROUND: A link between tendinopathy and oxidative stress has been recently reported. Nicotinamide mononucleotide (NMN) is a precursor of nicotinamide adenine dinucleotide, which plays an important role in cell redox homeostasis. The aim of this study was to evaluate the antioxidant effect of NMN on tendinopathy in vitro and in vivo. METHODS: Tenocytes from healthy Sprague-Dawley rats were cultured in regular glucose (RG) and high-glucose (HG) conditions with or without NMN, and were divided into four groups: RG NMN(-), RG NMN(+), HG NMN(-), and HG NMN(+). Cell viability, reactive oxygen species (ROS) accumulation, apoptotic rate, and mRNA expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX)1, NOX4, interleukin (IL)6, sirtuin (SIRT)1, and SIRT6 were investigated. In addition, rats with collagenase-induced tendinopathy were treated with or without NMN. Immunostaining of NOX1 and NOX4; mRNA expression of SIRT1, SIRT6, and IL6; and superoxide dismutase (SOD) activity measurements in the Achilles tendon were performed. RESULTS: NMN increased the expression of SIRT1 and SIRT6 in rat tenocytes, but decreased the levels of NOX1, NOX4, IL6, ROS, and apoptosis. In Achilles tendons with collagenase-induced tendinopathy, NMN increased the mRNA expression of SIRT1 and SIRT6, as well as SOD activity; while suppressing protein expression of NOX1 and NOX4, and mRNA expression of IL6. CONCLUSION: The in vitro and in vivo results of this study show that NMN exerts an antioxidant effect on tendinopathy by promoting the expression of SIRT while inhibiting that of NOX.

Effectiveness of combined extracorporeal shock-wave therapy and hyaluronic acid injections for patients with shoulder pain due to rotator cuff tendinopathy: a person-centered approach with a focus on gender differences to treatment response.

BACKGROUND: Rotator cuff (RC) tendinopathy is a common shoulder pain condition. Extracorporeal shockwave therapy (ESWT) and hyaluronic acid peritendinous injection are viable treatment options for RC tendinopathy. The aim of this study is to evaluate the response in two different therapeutic rehabilitative approaches, the combined treatment ESWT plus hyaluronic acid injections (E + Hy) compared to ESWT alone (ESWT-al), in a cohort of patients with RC tendinopathy according to gender differences. METHODS: This is a retrospective longitudinal cohort study of patients with painful RC tendinopathy. Patients that had received a clinical evaluation, a shoulder ultra sound examination, as well as the Shoulder Pain and Disability Index (SPADI) questionnaire, and the Numerical Rating Scale (NRS) for pain at baseline, 1-month (T1) and 2-month follow-ups (T2) were included. RESULTS: Medical records of 53 patients were analyzed. In the comparison between baseline to T1 and similarly from baseline to T2, a statistically significant reduction has been reported in the NRS (p < 0.001) and in the SPADI (p < 0.001) in the entire study group. At T1, patients in the E + Hy compared to ESWT-al group, showed a slight but statistically significant reductions in both NRS and SPADI score, while these changes were more evident at T2 (p < 0.001). Interestingly, a gender dimorphism in NRS and in SPADI was found, with female patients that apparently responded better to the combined E + Hy compared to ESWT-al approach. CONCLUSION: This retrospective cohort study suggests that the combination of ESWT plus HyA injections seems to be more effective than ESWT alone in RC tendinopathy in both genders. Moreover, in ESWT alone treatment, male patients reported better outcomes compared to females. However, further randomized controlled trials should be structured to confirm and enforce these conclusions.

17ß-Estradiol attenuates inflammation and tendon degeneration in a rat model of Achilles tendinitis.

INTRODUCTION: 17ß-Estradiol (E2) is an immune-regulatory agent with anti-inflammatory effects. However, it is still unknown whether E2 exerts pharmacological properties against Achilles tendinitis (AT). This study aims to investigate the effects of E2 on AT and its underlying mechanisms. MATERIALS AND METHODS: The established model of Achilles tendinitis was intraperitoneally injected with E2 (10, 20, or 30 µg/kg/d). After 8 weeks, biomechanical properties of the Achilles tendon were determined. Hydroxyproline content and tendon degeneration-related biomarkers were determined. The levels of inflammatory cytokines and apoptotic-related biomarkers in tendon tissues were determined. Furthermore, western blotting was determined to detect the expressions of ER-α and the PI3K/Akt pathway in tendon tissues. RESULTS: E2 relieved AT-related symptoms in a dose-dependent manner. E2 ameliorated tendon degeneration by regulating tendon degeneration-related biomarkers (e.g. collagen types I and III, Decorin (DCN), and tenascin-C). Besides, treatment with E2 suppressed inflammatory cytokines and increased anti-inflammatory cytokines. Treatment with E2 also regulated cell apoptosis in tendon tissues. The underlying mechanism study revealed that treatment with E2 activated ER-α and upregulated the PI3K/Akt pathway. CONCLUSION: The regulatory effects of E2 on inflammation and tendon degeneration in a rat model of AT were associated with the ER-α and the PI3K/Akt signaling pathways.

Roles of Oxidative Stress in Acute Tendon Injury and Degenerative Tendinopathy-A Target for Intervention.

Both acute and chronic tendon injuries are disabling sports medicine problems with no effective treatment at present. Sustained oxidative stress has been suggested as the major factor contributing to fibrosis and adhesion after acute tendon injury as well as pathological changes of degenerative tendinopathy. Numerous in vitro and in vivo studies have shown that the inhibition of oxidative stress can promote the tenogenic differentiation of tendon stem/progenitor cells, reduce tissue fibrosis and augment tendon repair. This review aims to systematically review the literature and summarize the clinical and pre-clinical evidence about the potential relationship of oxidative stress and tendon disorders. The literature in PubMed was searched using appropriate keywords. A total of 81 original pre-clinical and clinical articles directly related to the effects of oxidative stress and the activators or inhibitors of oxidative stress on the tendon were reviewed and included in this review article. The potential sources and mechanisms of oxidative stress in these debilitating tendon disorders is summarized. The anti-oxidative therapies that have been examined in the clinical and pre-clinical settings to reduce tendon fibrosis and adhesion or promote healing in tendinopathy are reviewed. The future research direction is also discussed.

Calebin A, a Compound of Turmeric, Down-Regulates Inflammation in Tenocytes by NF-κB/Scleraxis Signaling.

Calebin A (CA) is one of the active constituents of turmeric and has anti-inflammatory and antioxidant effects. Excessive inflammation and cell apoptosis are the main causes of tendinitis and tendinopathies. However, the role of CA in tendinitis is still unclear and needs to be studied in detail. Tenocytes in monolayer or 3D-alginate cultures in the multicellular tendinitis microenvironment (fibroblast cells) with T-lymphocytes (TN-ME) or with TNF-α or TNF-ß, were kept without treatment or treated with CA to study their range of actions in inflammation. We determined that CA blocked TNF-ß-, similar to TNF-α-induced adhesiveness of T-lymphocytes to tenocytes. Moreover, immunofluorescence and immunoblotting showed that CA, similar to BMS-345541 (specific IKK-inhibitor), suppressed T-lymphocytes, or the TNF-α- or TNF-ß-induced down-regulation of Collagen I, Tenomodulin, tenocyte-specific transcription factor (Scleraxis) and the up-regulation of NF-κB phosphorylation; thus, its translocation to the nucleus as well as various NF-κB-regulated proteins was implicated in inflammatory and degradative processes. Furthermore, CA significantly suppressed T-lymphocyte-induced signaling, similar to TNF-ß-induced signaling, and NF-κB activation by inhibiting the phosphorylation and degradation of IκBα (an NF-κB inhibitor) and IκB-kinase activity. Finally, inflammatory TN-ME induced the functional linkage between NF-κB and Scleraxis, proposing that a synergistic interaction between the two transcription factors is required for the initiation of tendinitis, whereas CA strongly attenuated this linkage and subsequent inflammation. For the first time, we suggest that CA modulates TN-ME-promoted inflammation in tenocytes, at least in part, via NF-κB/Scleraxis signaling. Thus, CA seems to be a potential bioactive compound for the prevention and treatment of tendinitis.