Histologic and biomechanical comparison of fascia lata autograft, acellular dermal xenograft, and synthetic patch for bridging massive rotator cuff tear in a rabbit model.

Background: Bridging repair has emerged as a promising and reliable treatment strategy for the massive rotator cuff tears (MRCTs). However, there remains a lack of evidence on which bridging graft provides the better repair results, and a dearth of animal studies comparing bridging repairs with different grafts. The purpose of this study was to evaluate the histological and biomechanical outcomes of commonly used grafts (autologous fascia lata (FL), acellular dermal matrix graft (ADM), and polyethylene terephthalate (PET) patch). Methods: A total of 66 male New Zealand White Rabbits were used to mimic a model of unilateral chronic MRCTs. The rabbits were randomly divided into three groups: (1) FL group, which underwent bridging repair with autologous FL; (2) ADM group, which underwent bridging with ADM; and (3) PET group, which underwent bridging with PET patch. Tissue samples were collected and subjected to histological analysis using Hematoxylin and eosin, Picrosirius red, Safranin O/Fast green staining, and Immunostaining. Collagen diameter and fibril density in the regenerated tendon was analyzed with transmission electron microscopy (TEM). Additionally, biomechanical tests were performed at 6 and 12 weeks after repair. Results: The regenerated tendon successfully reattached to the footprint in all experimental groups. At 6 weeks after repair, the FL group had a significantly higher Modified Tendon Histological Evaluation (MTHE) score at the regenerated tendon than the PET group (13.2 ± 1.64 vs 9.6 ± 1.95, respectively; P = 0.038). The picrosirius red staining results showed that the FL group had a significantly higher type I collagen content than the ADM and PET groups at 6 weeks, and this difference was sustained with the PET group at 12 weeks (P < 0.05). Immunofluorescence analysis against CD68 indicated that the number of macrophage infiltrates was significantly lower in the FL group than in the ADM and PET groups (P < 0.05). At 12 weeks after repair, the area of Safranin O metachromasia was significant greater in ADM group than that in the PET group (P = 0.01). The FL group showed a significantly larger collagen diameter in the regenerated tendon than the PET group (P < 0.05), as indicated by TEM results. Furthermore, the FL group resulted in a greater failure load (at 6 weeks; 118.40 ± 16.70 N vs 93.75 ± 9.06 N, respectively; P = 0.019) and elastic modulus (at 6 weeks; 12.28 ± 1.94 MPa vs 9.58 ± 0.79 MPa, respectively; P = 0.024; at 12 weeks; 15.02 ± 2.36 MPa vs 11.63 ± 1.20 MPa, respectively; P = 0.032) than the ADM group. Conclusions: This study demonstrated that all three grafts could successfully bridging chronic MRCTs in a rabbit model. However, autologous FL promoted tendon regeneration and maturation, and enhanced the tensile properties of the tendon-to-bone complex when compared with ADM and PET grafts.

Surgical management of chronic Achilles tendon rupture: evidence-based guidelines.

BACKGROUND: Chronic Achilles tendon ruptures (CATR) often require surgical intervention to restore function. Despite numerous treatment modalities available, the optimal management strategy remains controversial given the limited high-quality evidence available. This article aims to provide evidence-based guidelines for the surgical management of CATR through a comprehensive systematic review of the available data. The consensus reached by synthesizing the findings will assist clinicians in making informed decisions and improving patient outcomes. METHODS: A group of 9 foot surgeons in three continents was consulted to gather their expertise on guidelines regarding the surgical management of CATR. Following the proposal of 9 clinical topics, a thorough and comprehensive search of relevant literature published since 1980 was conducted for each topic using electronic databases, including PubMed, MEDLINE, and Cochrane Library, to identify relevant studies published until 1 October 2023. All authors collaborated in drafting, discussing, and finalizing the recommendations and statements. The recommendations were then categorized into two grades: grade a (strong) and grade b (weak), following the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) concept. Additionally, feedback from 21 external specialists, who were independent from the authors, was taken into account to further refine and finalize the clinical guidelines. RESULTS: Nine statements and guidelines were completed regarding surgical indications, surgical strategies, and postoperative rehabilitation protocol. CONCLUSION: Based on the findings of the systematic review, this guideline provides recommendations for the surgical management of CATR. We are confident that this guideline will serve as a valuable resource for physicians when making decisions regarding the surgical treatment of patients with CATR.

Rehabilitation increases cortical activation during single-leg stance in patients with chronic ankle instability.

Background: Chronic ankle instability (CAI) has been considered a neurophysiological disease, having as symptoms dysfunction in somatosensory and motor system excitability. Rehabilitation has been considered an effective treatment for CAI. However, few studies have explored the effects of rehabilitation on neuroplasticity in the CAI population. Objective: The purpose of this study was to investigate the effects of rehabilitation on cortical activities for postural control in CAI patients and to find the correlation between the change in cortical activities and patient-reported outcomes (PROs). Methods: Thirteen participants with CAI (6 female, 7 male, age = 33.8 ± 7.7 years, BMI = 24.7 ± 4.9 kg/m2) received a home exercise program for about 40 min per day, four days per week and six weeks, including ankle range-of-motion exercise, muscle strengthening, and balance activities. Cortical activation, PROs and Y-balance test outcomes were assessed and compared before and after rehabilitation. Cortical activation was detected via Functional near-infrared spectroscopy (fNIRS) while the participants performed single-leg stance tasks. Results: The participants had better PROs and Y balance test outcomes after rehabilitation. Greater cortical activation was observed in the primary somatosensory cortex (S1, d = 0.66, p = 0.035), the superior temporal gyrus (STG, d = 1.06, p = 0.002) and the middle temporal gyrus (MTG, d = 0.66, p = 0.035) in CAI patients after rehabilitation. Moreover, significant positive correlations were observed between the recovery of ankle symptoms and the change of cortical activation in S1 (r = 0.74, p = 0.005) and STG (r = 0.72, p = 0.007) respectively. Conclusion: The current study reveals that six weeks of rehabilitation can cause greater cortical activation in S1, STG and MTG. This increase in cortical activation suggested a better ability to perceive somatosensory stimuli and may have a compensatory role in function improvement.

Insufficient recovery of proprioception in chronic ankle instability after surgical restabilization: A systematic review.

Surgical repair or reconstruction of the lateral ligaments for patients with chronic ankle instability (CAI) could, logically, restore the proprioception of ankle through retensing receptors. To validate this hypothesis, seven databases were systematically searched, and thirteen studies comprising a total of 347 patients with CAI were included. Although five studies reported improved proprioceptive outcomes after surgeries, the other five studies with between-limb/group comparisons reported residual deficits at final follow-up, which does not consistently support proprioceptive recovery after existing surgical restabilization for CAI. More controlled studies are needed to provide evidence-based protocols to improve proprioceptive recovery after ankle restabilization for CAI.

Postural Control Deficits During Static Single-leg Stance in Chronic Ankle Instability: A Systematic Review and Meta-Analysis.

CONTEXT: Postural control deficits arising from injured ankles are central to chronic ankle instability (CAI) and its persistent symptoms. This is usually measured by recording the center of pressure (CoP) trajectory during static single-leg stance using a stable force plate. However, existing studies have produced conflicting results on whether this mode of measurement adequately reveals the postural deficits in CAI. OBJECTIVE: To determine whether postural control during static single-leg stance is impaired in CAI patients when compared with uninjured healthy controls. DATA SOURCES: Literature databases, PubMed, Embase, Web of Science, Cochrane Library, Scopus, CINAHL, and SPORTDiscus, were searched from inception to April 1, 2022, using ankle-, injury-, and posture-related terms. STUDY SELECTION: Two authors independently performed the step-by-step screening of article titles, abstracts, and full texts to select peer-reviewed studies investigating CoP trajectory during static single-leg stance using a stable force plate in CAI patients and healthy controls. A total of 13,637 studies were reviewed, and 38 studies (0.003%) met the selection criteria. STUDY DESIGN: Meta-analyses of descriptive epidemiological study. LEVEL OF EVIDENCE: Level 4. DATA EXTRACTION: CoP parameters, sway directions, visual condition, and numerical data (means and standard deviations) were extracted. RESULTS: The injured ankles of CAI patients had higher standard deviations of sway amplitude in both anterior-posterior and medial-lateral directions (standardized mean difference [SMD] = 0.36 and 0.31, respectively) under conditions of open eyes than controls. Higher mean sway velocity in anterior-posterior, medial-lateral, and total directions (SMD = 0.41, 0.37, and 0.45, respectively) with closed eyes was also found. CONCLUSION: CAI patients had deficits of postural control during static single-leg stance, and these deficits were identified by the CoP trajectory. Further methodological explorations of CoP parameters and corresponding test conditions are required to enhance the sensitivity and reliability of postural deficit assessments in CAI using force plates.

Bone marrow edema at ligament insertion is an accurate MRI sign of deltoid ligament injury.

BACKGROUND: Magnetic resonance imaging (MRI) is effective in diagnosing deltoid ligament (DL) injury but its sensitivity in chronic cases is low. Additional diagnostic signs are required to reduce the risk of a false negative diagnosis. PURPOSE: To evaluate the added diagnostic value of bone marrow edema at the ligament insertion (BMELI) of DL to the MRI assessment of chronic DL injury. MATERIAL AND METHODS: One hundred patients who consecutively came to our institution between November 2018 and December 2021 and underwent arthroscopic surgery for chronic ankle instability (CAI) were enrolled in the present study. Preoperative MR images were retrospectively reviewed by two orthopedic surgeons to evaluate the sensitivity, specificity and interobserver reliability of three MRI signs in diagnosing chronic DL injury, namely, abnormal ligamentous morphological characteristics (ALMC), BMELI and medial clear space (MCS). RESULTS: Taking arthroscopy as the reference standard, there were 34 patients with and 66 without DL injury. ALMC had 64.71% (22/34; 46.47-79.70) sensitivity and 83.33% (55/66; 71.71-91.00) specificity, BMELI had 70.59% (24/34; 52.33-84.29) sensitivity and 95.45% (63/66; 86.44-98.82) specificity and MCS had 26.47% (9/34; 13.51-44.65) sensitivity and 92.42% (61/66; 82.50-97.18) specificity. Compared with ALMC, BMELI had similar efficacy in superficial cases (P = 0.06) and greater efficacy in deep cases (P = 0.04). All three signs showed good interobserver agreement (kappa values all above 0.7). CONCLUSION: BMELI can reliably indicate concomitant injury to the DL in CAI patients. Using BMELI as a sign of chronic DL injury when ALMC is unclear may reduce the risk of a false negative diagnosis.

Prevalence and Injury Patterns of CFL Injury in Chronic Lateral Ankle Instability: An Observational Cross-Sectional Study Using Ultrasound.

The purpose of this paper is to assess the prevalence and injury patterns of the calcaneofibular ligament (CFL) in chronic lateral ankle instability (CAI) patients using ultrasound imaging. This retrospective study included 938 ankle ultrasound images from January 2016 to May 2018. The patients' demographic data and the injury pattern classified by the injury location and the remnant quality were recorded and correlated using t tests, Fisher's exact tests, and post hoc tests accordingly. Of the 938 CAI patients, CFL injury was found in 408/938 (44%). Among the 408 anterior talofibular ligament (ATFL) and CFL complex injury patients, 71/408 (17%) presented with a completely absorbed ATFL, whereas 13/71 (18%) presented with an absorbed CFL. The total CFL absorption proportion in all patients was relatively low (30/938 = 3%). Post hoc tests indicated a negative association between thickened ATFLs and complex injuries. In addition, a positive association existed between absorbed ATFLs and complex injuries as well as absorbed ATFLs and absorbed CFLs. Thus, the results indicated that total tearing and absorption injury patterns of the CFL in CAI are not common. Even when the ATFL is absorbed, only approximately one-fifth (13/71 = 18%) of CFLs require reconstruction, suggesting that it is unnecessary to routinely repair or reconstruct CFLs in all lateral ligament surgeries.

In Vivo Characterization of Cerebellar Peduncles in Chronic Ankle Instability: A Single and Multishell Diffusion-Weighted Imaging Study.

BACKGROUND: Ankle sprain causes proprioceptor injuries and prolonged joint deafferentation, which might lead to maladaptive neuroplasticity in patients with chronic ankle instability (CAI), especially in the cerebellum. Previous studies have indicated the impairment of superior cerebellar peduncle (SCP), but the inferior cerebellar peduncle (ICP) and middle cerebellar peduncle (MCP) have not been fully analyzed. HYPOTHESIS: The cerebellar peduncles of participants with CAI would have altered fractional anisotropy (FA) and orientation dispersion index (ODI) in comparison with healthy controls without ankle injury history. In addition, FA and ODI would be correlated with the duration or severity of the sensorimotor deficits in CAI. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: A group of 27 participants with CAI and 26 healthy controls underwent diffusion-weighted imaging scanning, with the cerebellar peduncles as the regions of interest. The measures obtained by single-shell diffusion tensor imaging and the multishell neurite orientation dispersion and density imaging were used. Correlation analyses were performed to examine the potential relationship between the FA/ODI and both the normalized Y-balance scores and the durations of ankle instability. RESULTS: The ipsilateral ICP of the injured ankle in participants with CAI showed significantly lower FA (Cohen d 95% CI, -1.33 to -0.21; P = 0.04) and marginally significant higher ODI (Cohen d 95% CI, 0.10 to 1.20, P = 0.08) when compared with the same measures in the control group, with the ODI being positively correlated with the duration of ankle instability (r = 0.42, P = 0.03). CONCLUSION: The ICP in participants with CAI exhibited impaired integrity and a trend of abnormally organized neurites in comparison with a healthy control group. CLINICAL RELEVANCE: The impairments of ICP might be an ongoing part of the pathological process of CAI, having the potential to become a target for the diagnostic evaluation of this clinical entity.

Satisfactory outcomes from the double-row fixation procedure for ankle lateral ligaments injury with os subfibulare.

Background: Ossicles of avulsed fractures of the lateral malleolus can result in pain or chronic ankle instability. The purpose of this study was to evaluate and compare the arthroscopic double-row fixation procedure with anatomic ankle lateral ligaments reconstruction for the treatment of ankle lateral ligaments injury with os subfibulare. Methods: This retrospective study included 38 patients with ankle lateral ligaments injury with concomitant os subfibulare who were treated between July 2016 and November 2021. The patients were divided into a double-row fixation group (n = 19) and an ankle lateral ligaments reconstruction group (n = 19). The Karlsson and Peterson Scoring System for Ankle Function (KAFS), American Orthopedic Foot and Ankle Society (AOFAS) score, Tegner score, visual analog scale (VAS), and anterior drawer test (ADT) were obtained preoperatively and at the last post-operative follow-up. Magnetic resonance imaging (MRI) was also performed at the last post-operative follow-up. Results: The KAFS, AOFAS, VAS, and Tegner scores increased significantly after the surgery. Furthermore, the pre- and post-operative functional scores were comparable between the two groups. The ADT was negative in all participants post-operatively. There were no significant differences between the double-row fixation and ligaments reconstruction groups regarding the proportions of patients who achieved a minimally clinically important difference (MCID) in KAFS, AOFAS, and Tegner scores. There was no significant difference in T2 mapping values for the tibial and talar side post-operatively between the two groups. Moreover, there were no significant differences in functional scores post-operatively between bony fusion and non-fusion patients in the double fixation group. Conclusion: The double-row fixation procedure provided similar satisfactory clinical outcomes when compared with lateral ligaments reconstruction for the treatment of ankle lateral ligaments injury with os subfibulare over a short follow-up duration.

A biomechanical comparison of the double-row suture fixation and compression screw techniques in the treatment of lateral malleolar avulsion fracture.

Background: Avulsion fractures of fibula occur with ankle sprains. The purpose of this study was to compare the biomechanical characteristics of double-row suture versus compression screw techniques in treatment of lateral malleolar avulsion fracturelarger than 10 mm in size, which is typically not associated with an anterior talofibular ligament injury. Methods: We simulated lateral malleolus avulsion fractures in six matched pairs of 12 human cadaveric ankles. These were then randomly divided into two groups: a double-row fixation group and a compression screw group. Biomechanical testing was performed after surgical fixation. The foot was rotated from the neutral position toward inversion at a rate of 1°/s until 12.5 N-m or structural failure was reached. The final rotation torque, rotation angle, stiffness, and displacement of the ossicles were recorded. Results: No significant difference was found in the final rotation torque (7.60 ± 3.70 vs 7.23 ± 2.06 N-m, p = 0.87), rotation angle (43.61 ± 14.77° vs 40.93 ± 10.94°, p = 0.56), stiffness (0.19 ± 0.08 vs 0.13 ± 0.07, p = 0.33), or displacement (6.11 ± 5.23 vs 7.09 ± 5.93 mm, p = 0.77) between the two groups. Conclusions: The stability of the double-row suture fixation was equivalent to compression screw fixation in treating a lateral malleolar avulsion fracture larger than 10 mm in size with ligament injury, as determined by our biomechanical testing.

Safe Talar Tunnel Placement During Reconstruction of the Deep Layer of the Deltoid Ligament: A Comparison of 4 Different Anatomic Landmarks on the Lateral Malleolus.

Background: Deltoid ligament reconstruction of the ankle can be considered when the ruptured ligament is insufficient for direct repair. Purpose: To compare the safety of talar tunnels oriented toward 4 different anatomic landmarks on the lateral malleolus during reconstruction of the deep layer of the deltoid ligament (DDL). Study Design: Descriptive laboratory study. Methods: A total of 30 computed tomography scans of the ankle joint in healthy adults were collected to generate 3-dimensional models. Virtual talar tunnels with a diameter of 5 mm and with different lengths (20.0, 25.0, and 30.0 mm) were created from the talar insertion of the DDL and were oriented toward the talar neck as well as the most anterior, the most distal, and the most posterior points of the distal fibula. The minimal safe distance (MSD) of a drilling route was calculated for the tunnels, and the safe distance from the end of the tunnel to the bone surface was measured for each tunnel. The nonpaired Student t test was used to detect differences among the safe distances of the 4 different bone tunnels. Results: For the 20.0-mm tunnels, the safe distance of the tunnel oriented toward the talar neck (5.90 ± 1.16 mm) did not meet the MSD (6.0 mm). For the 25.0-mm tunnels, the safe distances of the tunnels oriented toward the talar neck (4.53 ± 1.13 mm) and the anterior point of the fibula (5.91 ± 1.52 mm) did not meet the MSD (6.9 mm). Conclusion: Tunnels that were 5 mm in diameter and 20.0 and 25.0 mm in length, oriented toward the most distal or most posterior point of the distal fibula, were safe for DDL reconstruction. Clinical Relevance: Knowledge of safe talar tunnel placement is important, especially to avoid bone surface penetration during DDL reconstruction.

Thin and Plain Supplementary Motor Area in Chronic Ankle Instability: A Volume and Surface-based Morphometric Study.

CONTEXT: The supplementary motor area (SMA) is involved in the functional deficits of chronic ankle instability (CAI), but the structural basis of its abnormalities remains unclear. OBJECTIVE: To determine the differences in volume and surface-based morphological features of SMA between patients with CAI and healthy controls, and their relationship with the clinical features of CAI. DESIGN: Cross-sectional study. SETTING: Sports medicine laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 32 CAI patients (10 females; age: 32.46 ± 7.51 years) and 31 healthy controls (12 females; age: 29.70 ± 8.07 years) participated in this study. MAIN OUTCOME MEASURE(S): Participants perform T1 structural magnetic resonance imaging and calculate volume and surface-based morphological features of SMA subregions. These included anterior and posterior subdivisions of Brodmann's area 6 m (6 ma/6 mp), and supplementary and cingulate eye fields. Between-group comparisons and correlation analysis with clinical features of CAI were performed. RESULTS: Moderately thinner 6 mp (Cohen's d = -0.61) and moderately plainer 6 ma (Cohen's d = -0.70) were observed in patients compared with controls. Before and after regressing out the covariates, the thinner 6 mp was correlated with the lower foot and ankle ability measure scores of daily activities (r-before=0.400, r-after = 0.449). CONCLUSIONS: Patients with CAI had a thinner posterior subdivision (motor-output site) and a plainer anterior subdivision (motor-planning site) of SMA than that of controls. The thin motor-output site of the SMA is associated with ankle dysfunction in patients. These morphologic evidence of maladaptive neuroplasticity in SMA might promote more targeted rehabilitation of CAI.

Therapeutic effects following extracorporeal shock wave therapy for insertional and non-insertional Achilles tendinopathy.

Background: The treatment for Achilles tendinopathy varies widely, and there is no consensus regarding the optimal treatment for both non-insertional and insertional Achilles tendinopathy. The purpose of this study was to evaluate the clinical efficacy of extracorporeal shock wave therapy (ESWT) in the treatment of insertional and non-insertional Achilles tendinopathy (AT). Methods: Sixty patients with AT were invited to participate in this study. Patients were allocated to one of two groups according to the site of the AT, including an insertional AT (IAT) group and a non-insertional AT (NIAT) group. ESWT was performed once a week for five weeks for both groups. The Victorian Institute of Sport Assessment-Achilles questionnaire (VISA-A) score and the visual analog scale (VAS) were used five times to evaluate the clinical outcomes, including before treatment, immediately after treatment, as well as one month, three months, and five years after treatment. Results: At three months after treatment, the IAT group exhibited a significantly higher VISA-A score (82 ± 6 vs. 76 ± 11; p = 0.01) and a significantly lower VAS score (1 ± 1 vs. 2 ± 1; p < 0.001) when compared with the NIAT group. At the five-year assessment, the IAT group (1 ± 1) had a significantly lower VAS score than the NIAT group (2 ± 1) (p = 0.02), while no significant difference for the VISA-A score was observed between the groups (84 ± 8 vs. 84 ± 10; p = 0.98). Conclusions: Extracorporeal shock wave treatment can improve the symptoms of both insertional and non-insertional AT. The IAT patients experienced better clinical outcomes compared with the NIAT patients.

Arthroscopic repair with transosseous sling-suture technique for acute and chronic bony Bankart lesions.

Background: Failure to fix the fractured fragment can result in bony fragment resorption and consequent glenoid bone loss. Current arthroscopic repair techniques might lead to insecure fixation and refracture. The purpose of this study was to evaluate the effectiveness of the transosseous sling-suture technique for bony Bankart lesions, and to compare the clinical outcomes for acute and chronic bony Bankart lesions treated with this technique. Methods: A retrospective case series consisting of 46 patients with bony fracture of the glenoid rim following traumatic injury was identified from May 2015 to August 2020. The patients were divided into the acute lesion group and the chronic lesion group according to the time from first injury to surgery. The size of bone fragment was used to group the patients into the small and the medium sized fragment groups. All the patients underwent arthroscopic repairs using the transosseous sling-suture technique. Preoperative and postoperative evaluations including Rowe score, West Ontario Shoulder Instability Index (WOSI), Visual Analogue Scale (VAS) for pain scores, ROMs and number of dislocations were recorded. No significant differences were found in the comparisons of postoperative ROMs ang functional outcomes regarding between the small and the medium sized fragment groups. Results: No dislocations occurred for both groups postoperatively. At the last follow-up, all the ROMs (including anterior flexion, abduction, external rotation and internal rotation at the side), the Rowe score, the WOSI score and the VAS score for pain in the both groups were significantly improved compared to the preoperative evaluations (all Ps < 0.001). In the comparisons between the acute and the chronic lesion groups, significantly greater anterior flexion (158.9 ± 8.9° vs. 153.0 ± 6.4°, P = 0.037), abduction (167.7 ± 10.1° vs. 161.0 ± 7.0°, P = 0.035) and external rotation at the side (88.3 ± 6.4° vs. 83.5 ± 5.5°, P = 0.024) were found in the acute lesion group. The comparisons of the Rowe score (86.0 ± 7.5 vs. 87.5 ± 10.6, P = 0.319), the WOSI score (223.5 ± 56.3 vs. 185.0 ± 79.9, P = 0.062), the VAS score for pain (0.4 ± 0.2 vs. 0.3 ± 0.2, P = 0.324) and the internal rotation at the side (74.6 ± 13.2° vs. 80.5 ± 11.1°, P = 0.116) between these two groups did not demonstrate significant differences between the two groups. Conclusion: This arthroscopic transosseous sling-suture repair technique for shoulder anterior instability with acute and chronic bony Bankart lesion can restore joint stability, improve clinical outcomes and range of motion postoperatively. The acute bony Bankart lesion using the current technique can produce better range of motion compared to the chronic lesion. Study design: Retrospective case series; Level of evidence, 4.

Gene signature based on glycolysis is closely related to immune infiltration of patients with osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a degenerative arthritis with high levels of clinical heterogeneity. Aberrant metabolism such as shifting from oxidative phosphorylation to glycolysis is a response to changes in the inflammatory microenvironment of OA. Therefore, there is a pressing need to identify novel glycolysis regulators during OA progression. METHODS: We systematically studied glycolysis patterns mediated by 141 glycolysis regulators in 74 human synovial samples and discussed the characteristics of the immune microenvironment modified by glycolysis. The random forest (RF) method was applied to screen candidate hub glycolysis regulators in OA. RT-qPCR was performed to validate these key regulators. Then distinct glycolysis patterns were identified, and systematic correlation between these glycolysis patterns and immune cell infiltration was analyzed. The glycolysis score was constructed to quantify glycolysis patterns together with immune infiltration of individual OA patient. RESULTS: 56 glycolysis-related differentially expressed genes (DEGs) were identified between OA and non-OA samples. STC1, VEGFA, KDELR3, DDIT4 and PGAM1 were selected as candidate genes to predict the probability of OA. Two glycolysis patterns in OA were identified. Glycolysis cluster A with higher glycolysis score was related to an inflamed phenotype. CONCLUSIONS: Taken together, our results established a glycolysis-based genetic signature for OA, guided in-depth studies on the metabolic mechanism of OA, and facilitated to explore new clinical treatment strategies.

Contributions of joint damage-related events to gout pathogenesis: new insights from laboratory research.

Epidemiological and imaging findings indicate that gout frequently affects damaged joints. Recent studies suggest that the relationship between gout and joint damage may be more complex than a simple unidirectional link and that joint damage may promote the development of gout at affected sites. In this article, we review the clinical associations and recent laboratory research identifying events in the setting of osteoarthritis or joint injury that can alter the intraarticular microenvironment and locally regulate monosodium urate crystallisation and deposition or amplify the inflammatory response to deposited crystals. This includes cartilage matrix proteins or fibres released into the articular space that accelerates the crystallisation process, as well as the lack of lubricin and fibroblast priming that enhances the immune response towards the deposited crystals. These findings provide new insights into gout pathogenesis and offer a possible explanation for the site preference of gout in the damaged joint.

Identification of m7G-related hub biomarkers and m7G regulator expression pattern in immune landscape during the progression of osteoarthritis.

BACKGROUND: Accumulating evidence has shown that aberrant N7-methylguanosine (m7G) RNA methylation played an important role in the occurrence and development of cancer. However, knowledge of m7G modifications in inflammatory diseases is limited. Osteoarthritis (OA) is the most common arthritic disease with poor prognosis. Our research aimed to identify m7G-related hub biomarkers and investigate m7G regulator expression pattern in immune landscape of OA patients. METHODS: Gene expression profiles and their clinical information were obtained from the Gene Expression Omnibus (GEO) database, and differential analysis of 14 m7G-related regulators between elective OA and normal samples was performed. M7G-related hub genes for OA were mined based on single-sample gene set enrichment analysis (ssGSEA) and the random forest (RF) algorithm, and qRT-PCR was performed to confirm the abnormal expression of hub genes. Enrichment, protein-protein interaction (PPI), transcription factor (TF)-gene interaction and microRNA (miRNA)-gene coregulatory analysis based on m7G hub genes were performed. Then we predicted several candidate drugs related to m7G hub genes using DSigDB database. Moreover, we comprehensively evaluated m7G methylation patterns in OA samples and systematically correlated these modification patterns with the characteristics of immune cell infiltration. The m7G score was generated to quantify m7G methylation patterns for individual OA patients by the application of principal component analysis (PCA) algorithm. RESULTS: We constructed an OA predictive model based on 4 m7G hub genes (SNUPN, METTL1, EIF4E2 and CYFIP1). Two m7G methylation patterns in OA were discovered to show distinct biological characteristics, and an m7G score were generated. M7G cluster A and a higher m7G score were found to be related to an inflamed phenotype. CONCLUSIONS: Our study was the first to comprehensively investigate the m7G methylation dysregulations in immune landscape during the progression of OA. These 4 m7G gene-related signatures can be used as novel OA biomarkers to predict the occurrence of OA. Evaluating the m7G methylation patterns of OA individuals will contribute to enhancing our cognition of immune infiltration characterization and guiding more effective immunotherapy strategies.

Skeletal muscle-specific DJ-1 ablation-induced atrogenes expression and mitochondrial dysfunction contributing to muscular atrophy.

BACKGROUND: DJ-1 is a causative gene for Parkinson's disease. DJ-1-deficient mice develop gait-associated progressive behavioural abnormalities and hypoactive forearm grip strength. However, underlying activity mechanisms are not fully explored. METHODS: Western blotting and quantitative real-time polymerase chain reaction approaches were adopted to analyse DJ-1 expression in skeletal muscle from aged humans or mice and compared with young subjects. Skeletal muscle-specific-DJ-1 knockout (MDKO) mice were generated, followed by an assessment of the physical activity phenotypes (grip strength, maximal load capacity, and hanging, rotarod, and exercise capacity tests) of the MDKO and control mice on the chow diet. Muscular atrophy phenotypes (cross-sectional area and fibre types) were determined by imaging and quantitative real-time polymerase chain reaction. Mitochondrial function and skeletal muscle morphology were evaluated by oxygen consumption rate and electron microscopy, respectively. Tail suspension was applied to address disuse atrophy. RNA-seq analysis was performed to indicate molecular changes in muscles with DJ-1 ablation. Dual-luciferase reporter assays were employed to identify the promoter region of Trim63 and Fbxo32 genes, which were indirectly regulated by DJ-1 via the FoxO1 pathway. Cytoplasmic and nuclear fractions of DJ-1-deleted muscle cells were analysed by western blotting. Compound 23 was administered into the gastrocnemius muscle to mimic the of DJ-1 deletion effects. RESULTS: DJ-1 expression decreased in atrophied muscles of aged human (young men, n = 2; old with aged men, n = 2; young women, n = 2; old with aged women, n = 2) and immobilization mice (n = 6, P < 0.01). MDKO mice exhibited no body weight difference compared with control mice on the chow diet (Flox, n = 8; MDKO, n = 9). DJ-1-deficient muscles were slightly dystrophic (Flox, n = 7; MDKO, n = 8; P < 0.05), with impaired physical activities and oxidative capacity (n = 8, P < 0.01). In disuse-atrophic conditions, MDKO mice showed smaller cross-sectional area (n = 5, P < 0.01) and more central nuclei than control mice (Flox, n = 7; MDKO, n = 6; P < 0.05), without alteration in muscle fibre types (Flox, n = 6; MDKO, n = 7). Biochemical analysis indicated that reduced mitochondrial function and upregulated of atrogenes induced these changes. Furthermore, RNA-seq analysis revealed enhanced activity of the FoxO1 signalling pathway in DJ-1-ablated muscles, which was responsible for the induction of atrogenes. Finally, compound 23 (an inhibitor of DJ-1) could mimic the effects of DJ-1 ablation in vivo. CONCLUSIONS: Our results illuminate the crucial of skeletal muscle DJ-1 in the regulation of catabolic signals from mechanical stimulation, providing a therapeutic target for muscle wasting diseases.

Identification of four-gene signature to diagnose osteoarthritis through bioinformatics and machine learning methods.

BACKGROUND: Although osteoarthritis (OA) is one of the most prevalent joint disorders, effective biomarkers to diagnose OA are still unavailable. This study aimed to acquire some key synovial biomarkers (hub genes) and analyze their correlation with immune infiltration in OA. METHODS: Gene expression profiles and clinical characteristics of OA and healthy synovial samples were retrieved from the Gene Expression Omnibus (GEO) database. Hub genes for OA were mined based on a combination of weighted gene co-expression network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF) algorithms. A diagnostic nomogram model for OA prediction was developed based on the hub genes. Receiver operating characteristic curves (ROC) were performed to confirm the abnormal expression of hub genes in the experimemtal and validation datasets. qRT-PCR using patients' samples were conducted as well. In addition, the infiltration level of 28 immune cells in the expression profile and their relationship with hub genes were analyzed using single-sample GSEA (ssGSEA). RESULTS: 4 hub genes (ZBTB16, TNFSF11, SCRG1 and KDELR3) were obtained by WGCNA, lasso, SVM-RFE, RF algorithms as potential biomarkers for OA. The immune infiltration analyses revealed that hub genes were most correlated with regulatory T cell and natural killer cell. CONCLUSION: A machine learning model to diagnose OA based on ZBTB16, TNFSF11, SCRG1 and KDELR3 using synovial tissue was constructed, providing theoretical foundation and guideline for diagnostic and treatment targets in OA.

Bioinformatics and system biology approach to identify potential common pathogenesis for COVID-19 infection and osteoarthritis.

A growing of evidence has showed that patients with osteoarthritis (OA) had a higher coronavirus 2019 (COVID-19) infection rate and a poorer prognosis after infected it. Additionally, scientists have also discovered that COVID-19 infection might cause pathological changes in the musculoskeletal system. However, its mechanism is still not fully elucidated. This study aims to further explore the sharing pathogenesis of patients with both OA and COVID-19 infection and find candidate drugs. Gene expression profiles of OA (GSE51588) and COVID-19 (GSE147507) were obtained from the Gene Expression Omnibus (GEO) database. The common differentially expressed genes (DEGs) for both OA and COVID-19 were identified and several hub genes were extracted from them. Then gene and pathway enrichment analysis of the DEGs were performed; protein-protein interaction (PPI) network, transcription factor (TF)-gene regulatory network, TF-miRNA regulatory network and gene-disease association network were constructed based on the DEGs and hub genes. Finally, we predicted several candidate molecular drugs related to hub genes using DSigDB database. The receiver operating characteristic curve (ROC) was applied to evaluate the accuracy of hub genes in the diagnosis of both OA and COVID-19. In total, 83 overlapping DEGs were identified and selected for subsequent analyses. CXCR4, EGR2, ENO1, FASN, GATA6, HIST1H3H, HIST1H4H, HIST1H4I, HIST1H4K, MTHFD2, PDK1, TUBA4A, TUBB1 and TUBB3 were screened out as hub genes, and some showed preferable values as diagnostic markers for both OA and COVID-19. Several candidate molecular drugs, which are related to the hug genes, were identified. These sharing pathways and hub genes may provide new ideas for further mechanistic studies and guide more individual-based effective treatments for OA patients with COVID-19 infection.