More severe supraspinatus tendon degeneration on the contralateral shoulders in patients treated for symptomatic rotator cuff tears compared to healthy controls: a quantitative MRI-based study.

BACKGROUND: Patients treated for symptomatic rotator cuff tear (RCT) on one shoulder seem to have a higher prevalence of RCT on the contralateral shoulder. PURPOSE: To compare the supraspinatus (SSP) tendon and RC muscle properties on the contralateral shoulder in patients after repair surgery to those healthy individuals using quantitative magnetic resonance imaging (MRI). MATERIAL AND METHODS: A total of 23 patients treated for RCT (group A) and 23 healthy controls (group B) were recruited. Constant score, visual analog scale score (VAS), and MRI examinations were conducted. The SSP tendon structural status was graded based on the Zlatkin classification and quantified on ultrashort echo time (UTE)-T2* mapping images. Fatty degeneration of RC muscles was classified according to the Goutallier classification and quantified on T2 mapping. RESULTS: The Constant and VAS scores were comparable between groups A and B (all P >0.05). No significant differences were observed in tendon structural status between the two groups (P >0.05). However, significant differences were established in UTE-T2* values of the SSP tendon on the distal subregion between groups A and B (16.4 ± 2.4 ms vs. 14.8 ± 1.2 ms; P = 0.01). Regarding muscle degeneration, no significant differences were displayed in T2 values and Goutallier classification of RC muscles (all P >0.05). CONCLUSION: Patients with a treated RCT demonstrated inferior SSP tendon in the distal subregion on the contralateral shoulders one year postoperatively compared to that of healthy controls based on quantitative MRI data.

Role of tear size and tendon degeneration for development of pain in rat models of rotator cuff tear.

BACKGROUND: Rotator cuff tear (RCT) is a frequent etiology of shoulder pain and disability; however, the triggers for the onset and aggravation of pain remain obscure. In this study, we established novel rat RCT models to examine the impact of tear size and tendon degeneration on pain. METHODS: Fifty-five adult male Sprague-Dawley rats were allocated into 4 study groups: large tear (L group, n = 10), small tear (S group, n = 15), small tear with scratching (S+ group n = 15), and sham surgery (Sham group, n = 15). Pain-related behaviors were evaluated by weight distribution of forelimbs during a 5-minute free gait using a dynamic weight-bearing apparatus at 2, 4, 6, and 8 weeks. Calcitonin gene-related peptide (CGRP) expressions in ipsilateral dorsal root ganglion (DRG) neurons of C4, C5, and C6 were evaluated at 4 and 8 weeks. The area of scar tissues around the torn tendon, infiltration of inflammatory cells, and severity of tendon degeneration (modified Bonar score) were histologically assessed at 4 and 8 weeks. Additionally, enzyme-linked immunosorbent assay (ELISA) was conducted to evaluate the levels of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) expression in torn tendons and surrounding tissues at 4 weeks. RESULTS: The weight distribution ratio (ipsilateral and contralateral side) was significantly decreased in the L and S+ group compared with its baseline and Sham group (P < .05), but the S group showed no significant difference compared with the Sham. The ratio of CGRP-immunoreactive neurons in the DRGs was significantly higher in the L and S+ groups than in the S and Sham groups. The histologic assessment indicated that scar tissue formation was more extensive in the L group than in the S and S+ groups. Still, there was no significant difference between the S and S+ groups. The modified Bonar score was considerably higher in the S+ group than in the S group. Furthermore, ELISA analysis demonstrated no significant disparity in COX-2 levels between the groups; however, NGF levels were substantially higher in the S+ group than in the S and Sham groups. CONCLUSION: The present study provides compelling evidence that large RCT is strongly associated with heightened pain severity in a rat model. Nevertheless, even a small tear can significantly aggravate pain when the torn tendon is degenerated. CGRP upregulation driven by peripheral NGF possibly played a pivotal role in the genesis and exacerbation of pain in small RCT.

Factors associated with healing failure after early repair of acute, trauma-related rotator cuff tears.

BACKGROUND: Healing failure after rotator cuff repair is a challenging problem. Acute, trauma-related tears are considered a separate entity and are often treated surgically. The aim of this study was to identify factors associated with healing failure in previously asymptomatic patients with trauma-related rotator cuff tears treated with early arthroscopic repair. METHODS: This study included 62 consecutively recruited patients (23% women; median age, 61 years; age range, 42-75 years) with acute symptoms in a previously asymptomatic shoulder and a magnetic resonance imaging-verified full-thickness rotator cuff tear after shoulder trauma. All patients were offered, and underwent, early arthroscopic repair, during which a biopsy specimen was harvested from the supraspinatus tendon and analyzed for signs of degeneration. Of the patients, 57 (92%) completed 1-year follow-up and underwent assessment of repair integrity on magnetic resonance images according to the Sugaya classification. Risk factors for healing failure were investigated using a causal-relation diagram where age, body mass index, tendon degeneration (Bonar score), diabetes mellitus, fatty infiltration (FI), sex, smoking, tear location regarding integrity of the rotator cable, and tear size (number of ruptured tendons and tendon retraction) were included and analyzed. RESULTS: Healing failure at 1 year was identified in 37% of patients (n = 21). A high degree of FI of the supraspinatus muscle (P = .01), a tear location including disruption of rotator cable integrity (P = .01), and old age (P = .03) were associated with healing failure. Tendon degeneration as determined by histopathology was not associated with healing failure at 1-year follow-up (P = .63). CONCLUSION: Older age, increased FI of the supraspinatus muscle, and a tear including disruption of the rotator cable increased the risk of healing failure after early arthroscopic repair in patients with trauma-related full-thickness rotator cuff tears.

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.

No differences in histopathological degenerative changes found in acute, trauma-related rotator cuff tears compared with chronic, nontraumatic tears.

PURPOSE: Acute trauma-related rotator cuff tears are believed to have better healing potential than chronic tears due to less degenerative changes of the tendons. However, the histopathological condition of tendons from trauma-related tears is not well investigated. The purpose of this study was to explore specific histopathological features in tendons from acute trauma-related full-thickness rotator cuff tears and to compare them to findings in tendons from nontraumatic, chronic tears. METHODS: In a prospective cohort study, 62 previously asymptomatic patients [14 women, median age 61 years (range 42-75)] with trauma-related full-thickness rotator cuff tears were consecutively included. Arthroscopic repair was performed within 30 (median, IQR 25-37) days after the injury. During surgery, tissue biopsies were harvested from the supraspinatus tendons in 53 (86%) of the patients. In addition, similar biopsies were harvested from 10 patients undergoing surgery for chronic tears without history of trauma. All tissue samples were examined by a well-experienced pathologist under light microscope. Tendon degeneration was determined using the Bonar score whereas immunostaining was used for proliferation (Ki67), inflammation (CD45), apoptosis (p53) and haemosiderin staining to study traces of bleeding. RESULTS: The median (IQR) Bonar score for the acute trauma-related biopsies was 10.5 (7.5-14.5) compared to 11 (5-12.8) for the control group with no statistically significant difference between the groups. No statistically significant between-group difference was found for the inflammatory index whereas tendons from patients with trauma-related full-thickness rotator cuff tears had statistically significantly higher apoptosis [3.1 (0.5-8.9) vs. 0.1 (0-1.5), p = 0.003] and proliferation [4.0 (1.8-6.9) vs. 0.4 (0-2.0), p = 0.001) indices than those undergoing surgery for chronic tears. Positive haemosiderin staining was found in 34% of tissue samples from patients with trauma-related tears compared to 10% in the control group (n.s). CONCLUSION: This study suggests that there is no difference with regard to degenerative changes between supraspinatus tendons harvested from patients with acute, trauma-related rotator cuff tears and patients with nontraumatic, chronic tears. LEVEL OF EVIDENCE: II.

Insertional versus non-insertional tendoachilles tears: a comparative analysis of various predisposing factors and outcome following a repair.

BACKGROUND: Association of tendon degeneration, pre-existing posterior heel pain, Haglund's bump, retrocalcaneal spur, and mode of injury varies for the insertional and non-insertional type of tendoachilles tears (TA). PURPOSE: The study compares the various predisposing factors that determine the distinct type of TA tear and the outcome following a repair. METHODS: This is a retrospective study of the patients who underwent tendoachilles repair during January 2012-June 2018. Patients above 18 years with a minimum follow-up of two years were included. Patients with calcaneal tuberosity avulsions, prior surgeries, and open injuries were excluded. Patients were divided into groups 1 (insertional tears (IT)) and 2 (non-insertional tears (NIT)), and further subdivided based on the tendon degeneration (as D-degenerative and N-normal sub types) from ultrasound findings. AOFAS score and predisposing factors like degeneration, posterior heel pain, Haglund's bump, spur, and mechanism of injury were compared between the groups. RESULTS: The study included N = 146 with a mean age of 51.6 years and mean follow-up of 38.6 (range 24 to 96) months. IT associated with degeneration (IT-D) had a trivial fall as the predominant mechanism (P < 0.001). All patients had significant postoperative improvement of scores with no significant difference between the groups (P = 0.59) and subgroups (P = 0.27).75.34% had degenerative tendon, of which 64.5% were in the IT group and the rest in the NIT group (P = 0.02). 51.4% patients had a Haglund bump in the IT group and n.s. (P = 0.9). Forty-seven percent of patients had pre-existing posterior heel pain, 68% in IT and 32% in NIT (P = 0.04). Subgroup analysis revealed 65% of patients were in the IT-D subgroup (P < 0.001). CONCLUSION: Predisposing factors like posterior heel pain, tendon degeneration, and trivial trauma have a strong propensity for insertional TA tear. In contrast, the prominence of Haglund's bump does not predispose to a distinct type of TA tears. The outcome following a surgical repair-yields good results with no difference between the two groups.

The expression of substance P and calcitonin gene-related peptide is associated with the severity of tendon degeneration in lateral epicondylitis.

BACKGROUND: In this study, we investigated whether substance P (SP) or calcitonin gene-related peptide (CGRP) expression is associated with tendon degeneration in patients with lateral epicondylitis. METHODS: Twenty-nine patients who underwent surgical treatment for lateral epicondylitis were enrolled in the final analyses. Extensor carpi radialis brevis tendon origins were harvested for histological analysis. RESULTS: SP and CGRP immunostaining were negative in healthy tendons but positive in degenerative tendons; moreover, their immunoreactivity increased with degeneration severity. Univariate analysis indicated that variables such as the preoperative visual analog scale (VAS) score or SP or CGRP expression levels were significantly associated with the Movin score. However, multivariate analysis revealed that only higher SP and/or CGRP signals were associated with higher Movin scores. Elevations in SP or CGRP expression were also linked with significantly severe preoperative VAS scores. CONCLUSION: We demonstrated that tendon degeneration severity is associated with increased SP and CGRP expression in the biopsy samples of lateral epicondylitis.

Percutaneous Zadek osteotomy for the treatment of insertional Achilles tendinopathy.

BACKGROUND: Insertional Achilles tendinopathy (IAT) is a challenging common lower extremity disorder, despite several treatment options described in literature. Open dorsal closing wedge calcaneal osteotomy or Zadek Osteotomy (ZO), for the treatment of the IAT has good clinical results but a high rate of postoperative complications. The purpose of this study is to describe percutaneous ZO for the treatment of the IAT and to evaluate its impact on the clinical and functional postoperative outcomes. METHODS: Twenty-six consecutive patients presenting with unilateral IAT refractory to nonoperative measures were treated with percutaneous ZO. Visual Analogue Scale (VAS) and Foot Function Index Score (FFI) were recorded preoperatively and at final follow-up visit (12±3) months. Postoperative complications, satisfaction, and relief of the pain were also recorded. RESULTS: The percutaneous ZO showed a significant improvement (p<0.0001) in preoperative to postoperative FFI (from 65±9 to 8±12) and VAS (from 9±1 to 1±2). Two postoperative complications (8%) were observed: a case of symptomatic non-union and hardware pain, both in healthy patients. The overall rate of satisfaction after surgery was (92%). The relief from pain was achieved after an average period of 12 weeks. CONCLUSIONS: ZO is a safe and effective procedure for the treatment of IAT. The use of a minimally invasive surgical approach is associated with excellent pain reduction (VAS score) and improved clinical function (FFI score). When compared to the open surgical approach, the percutaneous ZO may decrease recovery time and postoperative complications. LEVEL OF EVIDENCE: III, retrospective case series.

Molecular changes to tendons after collagenase-induced acute tendon injury in a senescence-accelerated mouse model.

BACKGROUND: Aging impairs tendon healing and is a potential risk factor for chronic tendinitis. During normal aging, tendons undergo structural and biomechanical degenerative changes, accompanied by a reduction in the number of tenocytes and changes to their properties. However, molecular changes in aged tendons under inflammatory conditions are not well understood. The present study analyzed the molecular changes in collagenase induced acute tendon injury using a senescence-accelerated mouse (SAM) model. METHODS: SAMP6 mice were used as an aging animal model and SAMR1 mice were used as a control to represent a senescence-resistant inbred strain. All the mice used in the study were 40 weeks old. Collagenase I from Clostridium histolyticum (20 µL) was injected percutaneously to the tendon-bone junction of the Achilles tendon. Two weeks after treatment, the Achilles tendons were harvested and stained using Picrosirius Red to determine collagen expression. Real-time PCR was performed to analyze gene expression of IL-6, tenomodulin, type I and type II collagen, MMP-9, TIMP-1, and TIMP-2. RESULTS: Collagenase injection resulted in significantly higher gene expression of IL-6 but significantly lower tenomodulin expression compared with the control in SAMP6 and SAMR1 mice. In SAMP6 mice, gene expression of type III collagen and MMP-9 was significantly higher in the collagenase-injected group compared with the control group. SAMP6 mice also showed lower expression of type I collagen, TIMP-1, and TIMP-2 in the collagenase-injected group compared with the control group. Picrosirius Red staining showed the highest expression of type III collagen in the collagenase-injected SAMP6 group compared with the other groups. CONCLUSIONS: The collagenase-injected SAMP6 group showed higher expression of IL-6, MMP-9, and type III collagen and lower expression of type I collagen, TIMP-1, and TIMP-2, which are known to suppress metalloproteinases. The results indicate that aging may lead to dysfunction of the tendon healing process after acute tendon injury.

Fibrocartilaginous metaplasia identified in the long head of the biceps brachii.

BACKGROUND: In the glenohumeral joint, the long head of biceps brachii (LHBB) is exposed to tension and compression loading. The short head of biceps brachii (SHBB) works only in tension. It is known that tendon under compression might develop fibrocartilaginous metaplasia that improves the resistance to compression but reduces the resistance to tension. This study evaluated the presence of cartilage in LHBB and SHBB samples, supporting its possible role in tendon tear. METHODS: Between 2014 and 2016, 13 samples of LHBB and SHBB were collected during surgery for shoulder instability, glenohumeral arthritis, and massive rotator cuff tears. The samples were stained with hematoxylin and eosin, safranin-O, and Alcian blue (pH 1.0) for light microscopy. Immunohistochemistry was performed using anti-S100, anti-collagen I and II, and anti-tenascin-C antibodies. RESULTS: Histochemistry: LHBB samples showed matrix disorganization, with clusters of chondrocyte surrounded by collagen fibers and glycosaminoglycans. Safranin-O showed evident metachromasia. SHBB samples did not show any matrix disorganization or cartilaginous metaplasia. Immunohistochemistry: In all LHBB samples, anti-S100 and anti-collagen II showed cartilage in proximity of the tendon tear. Tenascin C immunostained closely to the disorganized matrix areas. SHBB, however, showed no positive areas for S-100, anti-collagen II, or tenascin C. CONCLUSIONS: According to our results, we hypothesize that the repeated stimulation in compression may induce the formation of fibrous cartilage. However, to date its role in tendon pathology remains to be clearly defined.

Macroscopic and histologic evaluation of a rat model of chronic rotator cuff tear.

BACKGROUND: The major cause of rotator cuff tears in humans is thought to be tendon degeneration. Although some studies have reported chronic rotator cuff tear models in animals, few studies of chronic rat models have demonstrated persistent defects for a relatively long time. The purpose of this study was to establish a chronic rotator cuff tear model in the rat and to evaluate the model macroscopically and histologically. METHODS: Sixty Sprague Dawley rats were divided into 2 groups: tendon detachment only (tear group) and tendon detachment plus figure resin (chronic group). The contralateral shoulder served as a sham-operated control (sham group). In the tear group, the supraspinatus and infraspinatus tendons were completely detached. In addition to cuff detachment, figure resin was placed on the greater tuberosity to prevent cuff reattachment and scar formation in the chronic group. Macroscopic and histologic changes were assessed at 4 and 12 weeks after surgery. RESULTS: A full-thickness cuff defect was observed in all chronic-group rats at both 4 and 12 weeks after surgery, and it could be repaired secondarily by traction in lower tension. However, no cuff defects were observed in the tear group because of obvious scar tissue formation. On histologic evaluation, progressive tendon degeneration, muscle atrophy, and fatty infiltration were observed in the chronic model at 12 weeks after surgery. CONCLUSION: We established a rat model of chronic rotator cuff tears using figure resin. This chronic rotator cuff tear model might be useful for further clinical investigations of rotator cuff repair.

The pathogenesis of Achilles tendinopathy: a systematic review.

Achilles tendinopathy is a degenerative, not an inflammatory, condition. It is prevalent in athletes involved in running sports. A systematic literature review on Achilles tendon tendinopathy has been performed according to the intrinsic (age, sex, body weight, tendon temperature, systemic diseases, muscle strength, flexibility, previous injuries and anatomical variants, genetic predisposition and blood supply) and extrinsic risk factors (drugs and overuse), which can cause tendon suffering and degeneration. Different theories have been found: Neurogenic, Angiogenic, Impingement and "Iceberg" Hypotheses. Multiple databases were utilized for articles published between 1964 and 2013. The different hypothesis were analyzed, differently considering those concerning the pathogenesis of tendinopathy and those concerning the etiology of complaints in patients. This review of the literature demonstrates the heterogeneity of Achilles tendinopathy pathogenesis. Various risk factors have been identified and have shown an interaction between them such as genes, age, circulating and local cytokine production, sex, biomechanics and body composition.

Pre-operative gluteus medius tendon degeneration and its impact on strength and functional ability one year after total hip replacement.

OBJECTIVE: Hip osteoarthritis is a common cause of disability and surgery is often unavoidable. Patient satisfaction is high and functional ability improves after surgery. However, residual impairment and pain are common. Degenerative changes in tendons and muscles are probable causes. The aim of this study is to investigate gluteus medius (GMED) tendon degeneration in relation to muscle strength, physical function and walking distance before and one year after total hip replacement. MATERIAL AND METHODS: In total, 18 patients were examined pre- and post-operatively, of whom 15 were available in the final analysis. Muscle strength, physical function and walking distance were assessed. Tendon biopsies were assessed microscopically, and the total degeneration score (TDS) was calculated. RESULTS: A correlation between the TDS and muscle strength was found for the hamstrings, GMED and quadriceps pre- or post-operatively. No correlations were found between the TDS and functional ability. Functional ability and muscle strength improved significantly after surgery. CONCLUSION: Our results indicate a correlation between tendon degeneration and the muscle strength of the hip and knee in patients with hip OA and one year after THR. To minimise post-operative residual discomfort, rehabilitation programs should probably be modified over time to match the pre- and post-operative needs. Further studies are needed.This study was registered at https://www.researchweb.org/is/vgr/project/279039 (in Swedish).

There are negative correlations, which suggest patterns between degeneration in the GMED tendon and muscle strength in the muscles acting around the hip in patients with hip OA, before and after THR.The strength training of muscles acting around the hip joint may need to be adjusted before and after THR.

Investigation of the Tissue Degenerative Impact of Increased BMI in Achilles Tendon via Strain Elastography and Finite Element Analysis.

BACKGROUND: This study is focused on establishing a relationship between poor muscle activity faced by obese individuals due to the change in stiffness of the intramuscular mass of the lower limb. This issue is also common among athletes and physically active teenagers. OBJECTIVE: The study is aimed at a subject assessment diagnosis technique named as Strain Elastography (SE) to measure muscle strain. Further, Finite Element Modelling (FEM) technique is used to investigate the strain and/or deformations generated in the Achilles Tendon (AT) models, which were categorized according to their Body Mass Index (BMI) through computationally applied loadings. METHODS: Total 54 volunteers with an average age of 21.85 ± 1.28 years were categorized into three groups according to their BMI (kg/m2); under BMI < 18.5 (n=14), normal BMI = 18.5-24.9 (n=20) and over BMI/obese > 25.0 (n=20). Additionally, multiple correlational analyses were performed between full range of BMI values and SE outcome. RESULTS: The presence of significant difference (p<0.05) was measured between different categories for BMI, BFMI, FFMI, DLFC, tendon length, tendon thickness and SR. Moreover, multiple correlational analyses and scatter plot strengthen the results. For FEM simulations, the maximum deformation was observed at the proximal end of the tendon in all three groups. CONCLUSION: It can be concluded that change in tendon stiffness and the resulting change in tendon structure was visualized with increased BMI. Moreover, obese individuals are more prone to tendon injury due to the increment in tendon thickness which causes bulging of the AT due to higher loads.

Achilles tendon degeneration on ultrasound in type 2 diabetic patients.

AIM OF STUDY: The main goal of this study was to compare the various degenerative changes in the Achilles tendon of type 2 diabetic patients to that of controls. The influence of diabetic peripheral neuropathy, duration of diabetes mellitus, age, and body mass index on the occurrence of degenerative changes was also evaluated. MATERIALS AND METHODS: The Achilles tendons of both limbs were evaluated with high-resolution ultrasound in 80 type 2 diabetics and 80 age/sex-matched controls. A 10 g Semmes Weinstein monofilament was used to examine for peripheral neuropathy. Anthropometric measurements and biochemical assessment of glycemic control (fasting plasma glucose and glycated hemoglobin) were also done. RESULTS: The mean age of type 2 diabetic subjects and healthy controls was 60.9 ± 10.3 years (range 41-79 years) and 61.0 ± 10.3 years (range 40-79 years), respectively (p = 0.963). The median duration of diabetes mellitus was 42.0 months (range = 1-456 months). The prevalence of degenerative changes (calcifications, disorganized fibers and/or hypoechoic foci) was significantly higher in type 2 diabetic subjects than controls in both the right (55.0% vs. 18.8%, p <0.001) and left (52.5% vs. 18.8%, p <0.001) feet. CONCLUSION: The Achilles tendons of type 2 diabetic subjects have significantly more degenerative changes than their age/ sex-matched controls in our locality. Disorganized Achilles tendon fibers occur significantly more often among male than female type 2 diabetic subjects. Disorganization of Achilles tendon fibers and hypoechoic foci are significantly more prevalent in type 2 diabetic subjects with peripheral neuropathy than those without peripheral neuropathy. Body mass index did not affect the occurrence of degenerative changes in the Achilles tendon of participants.

Cell autonomous TGFß signaling is essential for stem/progenitor cell recruitment into degenerative tendons.

Understanding cell recruitment in damaged tendons is critical for improvements in regenerative therapy. We recently reported that targeted disruption of transforming growth factor beta (TGFß) type II receptor in the tendon cell lineage (Tgfbr2ScxCre) resulted in resident tenocyte dedifferentiation and tendon deterioration in postnatal stages. Here we extend the analysis and identify direct recruitment of stem/progenitor cells into the degenerative mutant tendons. Cre-mediated lineage tracing indicates that these cells are not derived from tendon-ensheathing tissues or from a Scleraxis-expressing lineage, and they turned on tendon markers only upon entering the mutant tendons. Through immunohistochemistry and inducible gene deletion, we further find that the recruited cells originated from a Sox9-expressing lineage and their recruitment was dependent on cell autonomous TGFß signaling. The cells identified in this study thus differ from previous reports of cell recruitment into injured tendons and suggest a critical role for TGFß signaling in cell recruitment, providing insights that may support improvements in tendon repair.

MicroRNA Profiling Reveals Distinct Signatures in Degenerative Rotator Cuff Pathologies.

MicroRNAs (miRNAs) have emerged as key regulators orchestrating a wide range of inflammatory and fibrotic diseases. However, the role of miRNAs in degenerative shoulder joint disorders is poorly understood. The aim of this explorative case-control study was to identify pathology-related, circulating miRNAs in patients with chronic rotator cuff tendinopathy and degenerative rotator cuff tears (RCT). In 2017, 15 patients were prospectively enrolled and assigned to three groups based on the diagnosed pathology: (i) no shoulder pathology, (ii) chronic rotator cuff tendinopathy, and (iii) degenerative RCTs. In total, 14 patients were included. Venous blood samples ("liquid biopsies") were collected from each patient and serum levels of 187 miRNAs were determined. Subsequently, the change in expression of nine candidate miRNAs was verified in tendon biopsy samples, collected from patients who underwent arthroscopic shoulder surgery between 2015 and 2018. Overall, we identified several miRNAs to be progressively deregulated in sera from patients with either chronic rotator cuff tendinopathy or degenerative RCTs. Importantly, for the several of these miRNAs candidates repression was also evident in tendon biopsies harvested from patients who were treated for a supraspinatus tendon tear. As similar expression profiles were determined for tendon samples, the newly identified systemic miRNA signature has potential as novel diagnostic or prognostic biomarkers for degenerative rotator cuff pathologies. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. Inc. J Orthop Res 38:202-211, 2020.

Risk Factors for Rotator Cuff Disease: An Experimental Study on Intact Human Subscapularis Tendons.

Although several studies revealed a multifactorial pathogenesis of degenerative rotator cuff disorders, the impact and interaction of extrinsic variables is still poorly understood. Thus, this study aimed at uncovering the effect of patient- and pathology-specific risk factors that may contribute to degeneration of the rotator cuff tendons. Between 2015 and 2018, 54 patients who underwent arthroscopic shoulder surgery at three specialized shoulder clinics were prospectively included. Using tendon samples harvested from the macroscopically intact subscapularis (SSC) tendon, targeted messenger RNA expression profile analysis was performed in the first cohort (n = 38). Furthermore, histological analyses were conducted on tendon tissue samples obtained from a second cohort (n = 16). Overall, both study cohorts were comparable concerning patient demographics. Results were then analyzed with respect to specific extrinsic factors, such as patient age, body mass index, current as well as previous professions and sport activities, smoking habit, and systemic metabolic diseases. While patient age, sports-activity level, and preexisting rotator cuff lesions were considered to contribute most strongly to tendinopathogenesis, no further coherences were found. With regards to gene expression analysis, change in expression correlated most strongly with patient age and severity of the rotator cuff pathology. Further, chronic disorders increased overall gene expression variation. Taken together, our study provides further evidence that tendon degeneration is the consequence of a multifactorial process and pathological changes of the supraspinatus tendon affect the quality of SSC tendon and most likely vice versa. Therefore, the rotator cuff tendons need to be considered as a unit when managing rotator cuff pathologies. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 38:182-191, 2020.

Tgfß signaling is critical for maintenance of the tendon cell fate.

Studies of cell fate focus on specification, but little is known about maintenance of the differentiated state. In this study, we find that the mouse tendon cell fate requires continuous maintenance in vivo and identify an essential role for TGFß signaling in maintenance of the tendon cell fate. To examine the role of TGFß signaling in tenocyte function the TGFß type II receptor (Tgfbr2) was targeted in the Scleraxis-expressing cell lineage using the ScxCre deletor. Tendon development was not disrupted in mutant embryos, but shortly after birth tenocytes lost differentiation markers and reverted to a more stem/progenitor state. Viral reintroduction of Tgfbr2 to mutants prevented and even rescued tenocyte dedifferentiation suggesting a continuous and cell autonomous role for TGFß signaling in cell fate maintenance. These results uncover the critical importance of molecular pathways that maintain the differentiated cell fate and a key role for TGFß signaling in these processes.

Degenerative rotator cuff tears are associated with a low Omega-3 Index.

BACKGROUND: The etiology of degenerative rotator cuff tears is multifactorial but chronic inflammation plays an important role in the pathogenesis. Some polyunsaturated fatty acids (PUFA) can modulate inflammation and marine n-3 (Omega-3) PUFA have anti-inflammatory effects. We hypothesized that the Omega-3 Index is lower in patients with degenerative rotator cuff tears when compared to controls without rotator cuff tendinopathy. METHODS: From 684 consecutive patients with full thickness rotator cuff tears 655 were excluded because of possible bias. In the remaining 29 patients (22 m, 7 f; 53,9 y) with degenerative full thickness rotator-cuff tears, erythrocyte fatty acids were analyzed using the HS-Omega-3 Index® methodology. 15 healthy volunteers (10 m, 5 f; 52.5y) served as a control. RESULTS: The Omega-3 Index (% EPA + DHA) was 5.01% (95% CI: 3.81-4.66) in patients and 6.01% (95% CI: 4.48-5.72) in controls (p = 0.028) CONCLUSIONS: Patients with full thickness degenerative rotator cuff tears had a significantly lower Omega-3 Index than controls without rotator cuff tendinopathy. Whether a lower Omega-3 Index represents an independent risk factor for degenerative rotator cuff tears should be further investigated, e.g. in a longitudinal study.