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Elbow trauma can lead to joint contracture and reduced range of motion (ROM). Nonsurgical interventions can improve ROM, but in some cases capsule release surgery is required. Although surgery can improve ROM, it often does not restore full ROM. Thus, alternatives are needed. One approach is to target activated myofibroblasts, which are commonly associated with fibrotic tissue. Mechanical and biochemical cues drive a feedback loop that can result in normal or pathological healing. We hypothesize that this feedback loop exists in joint contracture and can be manipulated so that myofibroblast activity is reduced, normal healing is achieved, and ROM is improved. We previously demonstrated that blebbistatin can inhibit myofibroblast contractile forces and reduce collagen synthesis in vitro. Thus, the purpose of this study was to assess the use of blebbistatin in an animal model of elbow contracture, which was induced in 7 groups of 4 rats each (n = 28). All elbows were mechanically and histologically tested. The uninjured contralateral elbows of each rat were used as a control group. Capsule release surgery significantly improved (p < 0.01) outcomes 1 week after surgery compared to injury alone and was not significantly different from uninjured elbows. Three weeks after surgery, outcomes worsened, indicating joint stiffening consistent with what is observed clinically. The addition of blebbistatin did not significantly improve outcomes. Future work will investigate relationships among treatment, fibrotic tissue deposition, myofibroblast activity, and biomechanics to determine if blebbistatin is a useful adjunctive therapy for treating joint contracture., (© 2024 The Author(s). Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Purpose: Joint contracture is a common disease in clinical practice, joint bleeding is an important factor affecting the progression of joint contracture. This study aimed to explore the effect of extracorporeal shock wave on alleviating joint capsule fibrosis caused by intra-articular hemorrhage in rats., Methods: Forty two SD rats were randomly divided into seven groups. Perform simple fixation and fixation after blood injection separately. Measure the range of motion of each group's knee joints and calculate the corresponding degree of contraction. Use HE staining and Masson staining to detect the number of anterior joint capsule cells and collagen deposition. Detection of changes in Wnt1, β-catenin protein expression in joint capsule using Western blotting., Results: Compared to group C, the degree of knee joint contracture in M1 and M2 groups of rats increased, and collagen deposition, cell number and Wnt1, β-catenin protein expression also increased accordingly. Compared to M1 and M2 groups, the degree of knee contraction in E1 and E2 groups were reduced, while collagen deposition, cell number and Wnt1, β-catenin protein expression were decreased, and the degree of joint contracture in NR1 and NR2 groups showed no significant improvement. Compared to NR1 and NR2 groups, the degree of knee contraction in E1 and E2 groups were reduced, while collagen deposition, cell number and Wnt1, β-catenin protein expression were decreased., Conclusions: Both rat models of knee joint contracture were successful, and joint bleeding can exacerbate joint contracture. Extracorporeal shock waves alleviate joint capsule fibrosis caused by intra-articular bleeding in rats.

Background and Objectives: This study aimed to evaluate the relationship between SLAP lesions and the shoulder joint capsule thickness via MR arthrography. Understanding the relationship between SLAP lesions and the joint capsule thickness is important because an increased capsule thickness may indicate chronic inflammation and contribute to persistent pain and dysfunction. These findings have significant clinical implications for the diagnosis, management, and treatment strategies of shoulder joint pathologies. Materials and Methods: We retrospectively analyzed the MR arthrography results of 78 patients who underwent shoulder imaging at Düzce University Medical Faculty between October 2021 and November 2024. The study included patients diagnosed with SLAP lesions and compared them with a control group without such pathology. Data on joint capsule thickness at the level of the axillary recess, SLAP lesion type, cuff pathology, and demographic information were collected and analyzed. Results: The study included 32 patients with SLAP lesions and 46 control subjects. The mean age of the patients was 44.75 ± 14.18 years, whereas the control group had a mean age of 38.76 ± 13 years. The patient group presented a significantly greater mean anterior capsule thickness (3.13 ± 1.28 mm vs. 1.72 ± 0.7 mm, p = 0.0001), posterior capsule thickness (3.35 ± 1.32 mm vs. 1.95 ± 1.06 mm, p = 0.0001), and maximum capsule thickness (3.6 ± 1.32 mm vs. 2.06 ± 1.01 mm, p = 0.0001) in the axillary recess. SLAP type 2 lesions were the most common type (43.76%) in the patient group. Conclusions: This study revealed a significant association between SLAP lesions and an increased shoulder joint capsule thickness. These findings suggest that MR arthrography is an effective tool for assessing the joint capsule changes associated with labral tears, contributing to the better diagnosis and management of shoulder joint pathologies in clinical practice.

Femoroacetabular impingement (FAI), characterized by a pathological contact between the proximal femur and acetabulum, is a common precursor of hip osteoarthritis. Cam morphology is a bony prominence that causes FAI and frequently forms on the anterosuperior femoral head-neck junction. Despite anatomical consensus regarding the femoral head-neck junction as a boundary area covered by the articular cartilage and joint capsule, it remains unclear whether the joint capsule is continuous with the anterosuperior articular cartilage. For the anatomical consideration of cam morphology formation, this study aimed to investigate the histological characteristics of the capsular attachment on the anterosuperior femoral head-neck junction, particularly focusing on the presence or absence of continuity of the joint capsule to the articular cartilage. A total of 21 anterosuperior regions (seven hips each for the 12:00, 1:30, and 3:00 positions) from seven hips (three males and four females; mean age at death, 68.7 years) were histologically analyzed in this study for quantitative evaluation of the capsular thickness using histological sections stained with Masson's trichrome, as well as qualitative evaluation of the capsular attachment. The present study showed that the joint capsule, which folded proximally to the femoral head-neck junction from the recess, exhibited a blend of the fibrous and synovial regions. Notably, it not only continued with the superficial layer of the articular cartilage, but also attached to the articular cartilage via the fibrocartilage. This continuous region was relatively fibrous with dense connective tissue running in the longitudinal direction. The capsular thickness at the recess point (mean, 1.7 ± 0.9 mm) and those at the distal end of the articular cartilage (0.35 ± 0.16 mm) were significantly greater than the control value for the most superficial layer thickness of the articular cartilage (0.019 ± 0.003 mm) (Dunnett's T3, both p-value <0.001). Based on the fibrous continuity between the joint capsule and articular cartilage and its thickness, this study suggests the anatomical possibility that some mechanical stress can be transmitted from the joint capsule to the articular cartilage at the frequent sites of cam morphology., (© 2024 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

Objective: The goals of this study were (i) to assess the association between hip capsule morphology and pain in patients without any other MRI abnormalities that would correlate with pain and (ii) to investigate whether hip capsule morphology in hip pain patients is different from that of controls., Methods: In this study, 76 adults with hip pain who did not show any structural abnormalities on MRI and 46 asymptomatic volunteers were included. Manual segmentation of the anterior and posterior hip capsules was performed. Total and mean anterior hip capsule area, posterior capsule area, anterior-to-posterior capsule area ratio, and medial-to-lateral area ratio in the anterior capsule were quantified. Differences between the pain and control groups were evaluated using logistic regression models., Results: Patients with hip pain showed a significantly lower anterior-to-posterior area ratio as compared with the control group (p = 0.002). The pain group's posterior hip capsule area was significantly larger than that of controls (p = 0.001). Additionally, the ratio between the medial and lateral sections of the anterior capsule was significantly lower in the pain group (p = 0.004)., Conclusions: Patients with hip pain are more likely to have thicker posterior capsules and a lower ratio of the anterior-to-posterior capsule area and thinner medial anterior capsules with a lower ratio of the medial-to-lateral anterior hip capsule compartment, compared with controls., Clinical Relevance Statement: During MRI evaluations of patients with hip pain, morphology of the hip capsule should be assessed. This study aims to be a foundation for future analyses to identify thresholds distinguishing normal from abnormal hip capsule measurements., Key Points: • Even with modern image modalities such as MRI, one of the biggest challenges in handling hip pain patients is finding a structural link for their pain. • Hip capsule morphologies that correlated with hip pain showed a larger posterior hip capsule area and a lower anterior-to-posterior capsule area ratio, as well as a smaller medial anterior capsule area with a lower medial-to-lateral anterior hip capsule ratio. • The hip capsule morphology is correlated with hip pain in patients who do not show other morphology abnormalities in MRI and should get more attention in clinical practice., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Joint contracture is one of the common diseases clinically, and joint capsule fibrosis is considered to be one of the most important pathological changes of joint contracture. However, the underlying mechanism of joint capsule fibrosis is still controversial. The present study aims to establish an animal model of knee extending joint contracture in rats, and to investigate the role of hypoxia-mediated pyroptosis in the progression of joint contracture using this animal model. 36 male SD rats were selected, 6 of which were not immobilized and were used as control group, while 30 rats were divided into I-1 group (immobilized for 1 week following 7 weeks of free movement), I-2 group (immobilized for 2 weeks following 6 weeks of free movement), I-4 group (immobilized for 4 weeks following 4 weeks of free movement), I-6 group (immobilized for 6 weeks following 2 weeks of free movement) and I-8 group (immobilized for 8 weeks) according to different immobilizing time. The progression of joint contracture was assessed by the measurement of knee joint range of motion, collagen deposition in joint capsule was examined with Masson staining, protein expression levels of HIF-1α, NLRP3, Caspase-1, GSDMD-N, TGF-β1, α-SMA and p-Smad3 in joint capsule were assessed using western blotting, and the morphological changes of fibroblasts were observed by transmission electron microscopy. The degree of total and arthrogenic contracture progressed from the first week and lasted until the first eight weeks after immobilization. The degree of total and arthrogenic contracture progressed rapidly in the first four weeks after immobilization and then progressed slowly. Masson staining indicated that collagen deposition in joint capsule gradually increased in the first 8 weeks following immobilization. Western blotting analysis showed that the protein levels of HIF-1α continued to increase during the first 8 weeks of immobilization, and the protein levels of pyroptosis-related proteins NLRP3, Caspase-1, GSDMD-N continued to increase in the first 4 weeks after immobilization and then decreased. The protein levels of fibrosis-related proteins TGF-β1, p-Smad3 and α-SMA continued to increase in the first 8 weeks after immobilization. Transmission electron microscopy showed that 4 weeks of immobilization induced cell membrane rupture and cell contents overflow, which further indicated the activation of pyroptosis. Knee extending joint contracture animal model can be established by external immobilization orthosis in rats, and the activation of hypoxia-mediated pyroptosis may play a stimulating role in the process of joint capsule fibrosis and joint contracture., (© 2024. The Author(s).)

Objective: The aim of the work described here was to investigate the efficacy and potential mechanisms of low-intensity pulsed ultrasound (LIPUS) for the treatment of arthrogenic contracture induced by immobilization in rabbits., Methods: The left knee joint of rabbits was immobilized for 6 wk to establish the model of extending knee joint contracture. The rabbits were divided into a control group (C), a group immobilized for 6 wk (IM-6w), a group remobilized for 1 wk (RM-1w), a group subjected to LIPUS intervention for 1 wk (LIPUS-1w), a group remobilized for 2 wk (RM-2w) and a group subjected to LIPUS intervention for 2 wk (LIPUS-2w). The degrees of arthrogenic contracture and joint capsule fibrosis were assessed, as were the levels of reactive oxygen species (ROS) and the activation status of the TGF-β1/Smad signaling pathway in the joint capsule., Results: After immobilization for 6 wk, the degrees of arthrogenic contracture and joint capsule fibrosis increased. The ROS level increased, as evidenced by an increase in malondialdehyde content and a decrease in superoxide dismutase content. In addition, the TGF-β1/Smad signaling pathway was significantly activated. The degrees of knee joint contracture increased in the first week after remobilization and decreased in the second week. Furthermore, joint capsule fibrosis continued to develop during the 2 wk of remobilization, and the ROS level increased, while the TGF-β1/Smad signaling pathway was significantly activated. LIPUS effectively reduced the level of ROS in the joint capsule, which further inhibited activation of the TGF-β1/Smad signaling pathway, thereby improving joint capsule fibrosis and reducing arthrogenic contracture., Conclusion: The high ROS levels and overactivation of the TGF-β1/Smad signaling pathway may be reasons why immobilization induces knee joint capsule fibrosis. LIPUS can alleviate the degree of knee joint capsule fibrosis induced by immobilization by inhibiting the production of ROS and the activation of the TGF-β1/Smad signaling pathway., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to observe the therapeutic effect of extracorporeal shock wave (ESW) on extensional joint contracture of knee joint in rats and its mechanism on articular capsule fibrosis. Thirty-two SD rats were randomly divided into blank control, immobilization, natural recovery, and ESW intervention groups. Except for the control group, the left knee joints of other rats were fixed with external fixation brace for 4 weeks when they were fully extended to form joint contracture. The effect of intervention was assessed by evaluating joint contracture, total cell count and collagen deposition in joint capsule, and protein expression levels of TGF-β1, p-Smad2/3, Smad2/3, p-JNK, JNK, I and III collagen in joint capsule. ESW can effectively reduce arthrogenic contracture, improve the histopathological changes of anterior joint capsule, inhibit the high expression of target protein and the excessive activation of TGF-β1/Smad2/3/JNK signal pathway. Inhibition of excessive activation of TGF-β1/Smad2/3/JNK pathway may be one of the potential molecular mechanisms by which extracorporeal shock wave can play a role.

Adhesive capsulitis, colloquially known as "frozen shoulder," is a relatively common disorder, affecting approximately 2% to 5% of the general population. The incidence may be higher as the condition can be relatively mild and self-limited and thus many patients who experience it may never present for treatment. It involves a pathologic process of gradual fibrosis of the glenohumeral joint that leads to limited active and passive range of motion, contracture of the joint capsule, and shoulder pain., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Joint immobilization, which ensures rest and accelerates tissue recovery in musculoskeletal disorders, often causes joint contracture, for which there is still no effective prevention. To address this, we investigated the effects of extracorporeal shockwave therapy (ESWT) in preventing joint contracture, in a unilaterally immobilized knee rat model. Under general anesthesia, ESWT (0.25 mJ/mm 2 , 3000 shot, 4 Hz, 3 days/week) was administered from 1 day after immobilization up to 2, 4, and 6 weeks. The immobilized control group received general anesthesia without ESWT. We evaluated joint angle, tissue elasticity, and gene and protein expression related to fibrosis, inflammation, and angiogenesis in the joint capsule. Relative to the control, the ESWT group had greater joint angle at 4 and 6 weeks, and lower posterior-capsule elasticity at 6 weeks. In the ESWT group, at 6 weeks, gene expression of collagen type I (col1α1), connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA) was significantly downregulated, whereas interleukin-6 (IL-6) and hypoxia-inducible factor-1α (HIF-1α) gene expression was upregulated, relative to that in the control. Compared with that in the control, at 4 and 6 weeks, the ratio of CTGF + cells was significantly lower in the ESWT group; at 4 weeks, the ESWT group had significantly fewer CD68 + cells in the adhesion area, and at 6 weeks, significantly more blood vessels. Statement of Clinical Significance: In a rat model, ESWT counteracted fibrosis, suppressed macrophage infiltration, and promoted neovascularization, reducing elasticity, and increasing joint range-ofmotion. ESWT offers a potential new strategy to prevent progression in joint contracture., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Arthrofibrosis, or rigid contracture of major articular joints, is a significant morbidity of many neurodegenerative disorders. The pathogenesis depends on the mechanism and severity of the precipitating neuromuscular disorder. Most neuromuscular disorders, whether spastic or hypotonic, culminate in decreased joint range of motion. Limited range of motion precipitates a cascade of pathophysiological changes in the muscle-tendon unit, the joint capsule, and the articular cartilage. Resulting joint contractures limit functional mobility, posing both physical and psychosocial burdens to patients, economic burdens on the healthcare system, and lost productivity to society. This article reviews the pathophysiology of arthrofibrosis in the setting of neuromuscular disorders. We describe current non-surgical and surgical interventions for treating arthrofibrosis of commonly affected joints. In addition, we preview several promising modalities under development to ameliorate arthrofibrosis non-surgically and discuss limitations in the field of arthrofibrosis secondary to neuromuscular disorders., (© 2022. The Author(s).)

Aims: Several studies have used animal models to examine knee joint contracture; however, few reports detail the construction process of a knee joint contracture model in a mouse. The use of mouse models is beneficial, as genetically modified mice can be used to investigate the pathogenesis of joint contracture. Compared to others, mouse models are associated with a lower cost to evaluate therapeutic effects. Here, we describe a novel knee contracture mouse model by immobilization using external fixation., Methods: The knee joints of mice were immobilized by external fixation using a splint and tape. The passive extension range of motion (ROM), histological and immunohistochemical changes, and expression levels of fibrosis-related genes at 2 and 4 weeks were compared between the immobilized (Im group) and non-immobilized (Non-Im group) groups., Results: The extension ROM at 4 weeks was significantly lower in the Im group than in the Non-Im group (p < 0.01). At 2 and 4 weeks, the thickness and area of the joint capsule were significantly greater in the Im group than in the Non-Im group (p < 0.01 in all cases). At 2 weeks, the mRNA expression levels of the fibrosis-related genes, except for the transforming growth factor-β1 , and the protein levels of cellular communication network factor 2 and vimentin in the joint capsule were significantly higher in the Im group (p < 0.01 in all cases)., Conclusion: This mouse model may serve as a useful tool to investigate the etiology of joint contracture and establish new treatment methods.

Background: The evaluation of the natural history prevalence of adverse local tissue reactions (ALTRs) using MRI has focused only on metal-on-metal (MoM) bearing surfaces without comparison to nonMoM bearing surfaces., Questions/purposes: To determine (1) the longitudinal changes and differences in blood metal ion levels in patients with hip resurfacing arthroplasty (HRA), ceramic-on-ceramic (CoC) THA, and metal-on-polyethylene (MoP) THA compared with those undergoing ceramic-on-polyethylene (CoP) THA; (2) how the longitudinal change of synovial reaction classification in patients with HRA, CoC THA, and MoP THA compares with those undergoing CoP THA, and whether there is an association between the presence of an ALTR or metallosis on MRI with corresponding patient-reported outcomes, or the presence of capsular dehiscence; and (3) differences in blood metal ion levels between patients undergoing HRA with an ALTR or metallosis on MRI and those with HRA without these conditions., Methods: Between March 2014 and February 2019, 22,723 patients underwent primary HRA and THA at one center. Patients received an HRA based on their desired athletic level after surgery and the presence of normal acetabular and proximal femoral bone morphology without osteopenia or osteoporosis. Two percent (342 of 22,723) of patients were contacted to participate, and 71% (243 of 342 hips in 206 patients) were enrolled for analysis at baseline. The patients underwent arthroplasty for degenerative joint disease, and 25 patients withdrew over the course of the study. We included patients who were more than 1 year postarthroplasty. All participants had an MRI examination and blood serum ion testing and completed a Hip Disability and Osteoarthritis Outcome Score survey annually for four years (baseline, year 1, year 2, year 3). Morphologic and susceptibility-reduced MR images were evaluated by a single radiologist not involved in the care of patients for the presence and classification of synovitis (Gwet AC1: 0.65 to 0.97), synovial thickness, and volume (coefficient of repeatability: 1.8 cm3). Linear mixed-effects models were used to compare the mean synovial thickness, synovial volume, and Hip Disability and Osteoarthritis Outcome Score subscales between bearing surfaces at each timepoint and within each bearing surface over time. Marginal Cox proportional hazards models were used to compare the time to and the risk of developing ALTR only, metallosis only, and ALTR or metallosis between bearing surfaces. All models were adjusted for age, sex, BMI, and length of implantation based on known confounders for hip arthroplasty. Adjustment for multiple comparisons was performed using the Dunnett-Hsu method., Results: Patients with unilateral HRA had higher cobalt and chromium serum ion levels (baseline: 1.8 ± 0.8 ppb, year 1: 2.0 ± 1.5 ppb, year 2: 2.1 ± 1.2 ppb, year 3: 1.6 ± 0.7 ppb) than those with unilateral CoP bearings (baseline: 0.0 ± 0.1 ppb, year 1: 0.1 ± 0.3 ppb, year 2: 0.0 ± 0.2 ppb, year 3: 0.0 ± 0.0 ppb) at all timepoints (p < 0.001 for each time point). More patients who received an HRA developed ALTR or metallosis on MRI than did patients with CoP bearings (hazard ratio 4.8 [95% confidence interval 1.2 to 18.4]; p = 0.02). There was no association between the longitudinal change of synovial reaction to ALTR or metallosis on MRI with patient-reported outcomes. In addition, there was no association between the presence of dehiscence at baseline and the subsequent development of ALTR or metallosis, as seen on MRI. There were elevated cobalt (4.7 ± 3.5 ppb) and chromium (4.7 ± 2.6 ppb) serum levels in patients with unilateral HRA who had an ALTR or metallosis present on MRI at year 1 compared with patients without an ALTR or metallosis on MRI (cobalt: 1.8 ± 1.0 ppb, mean difference 4.7 ppb [95% CI 3.3 to 6.0]; p < 0.001; chromium: 2.3 ± 0.5 ppb, mean difference 3.6 ppb [95% CI 2.2 to 5.0]; p < 0.001) as well as for chromium at year 3 (3.9 ± 2.4 ppb versus 2.2 ± 1.1 ppb, mean difference 1.3 ppb [95% CI 0.3 to 2.4]; p = 0.01)., Conclusion: We found a higher proportion of ALTR or metallosis on MRI in patients with HRA compared with patients with CoP, even when patient self-assessed symptomatology of those with an ALTR or metallosis on MRI was not different than the absence of these features. MRI detected ALTRs in high-function patients, emphasizing that an annual clinical assessment dependent on survey or blood ion testing alone may not detect soft tissue complications. The results of this study are in line with prior consensus recommendations of using MRI as part of a routine follow-up protocol for this patient population., Level of Evidence: Level III, therapeutic study., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2021 by the Association of Bone and Joint Surgeons.)

Joint contracture leads to major patient discomfort. Metformin, one of the most extensively used oral drugs against type 2 diabetes has recently been found to suppress tissue fibrosis as well. However, its role in suppressing tissue fibrosis in joint contractures remains unknown. In this study, we examined the role of metformin treatment in suppressing joint capsular fibrosis and the most effective time of its administration. Joint capsular fibrosis was induced by immobilizing the knee joints of mice using splints and tapes. Metformin was administered intraperitoneally every alternate day after immobilization. Histological and immunohistochemical changes and expression of fibrosis-related genes were evaluated. Metformin treatment significantly suppressed fibrosis in joint capsules based on histological and immunohistochemical evaluation. Joint capsular tissue from metformin-treated mice also showed decreased expression of fibrosis-related genes. Early, but not late, metformin administration showed the same effect on fibrosis suppression in joint capsule as the whole treatment period. The expression of fibrosis-related genes was most suppressed in mice administered with metformin early. These studies demonstrated that metformin treatment can suppress joint capsular fibrosis and the most effective time to administer it is early after joint immobilization; a delay of more than 2 weeks of administration is less effective., (© 2021. The Author(s).)

Posttraumatic fibrotic scarring is a significant medical problem that alters the proper functioning of injured tissues. Current methods to reduce posttraumatic fibrosis rely on anti-inflammatory and anti-proliferative agents with broad intracellular targets. As a result, their use is not fully effective and may cause unwanted side effects. Our group previously demonstrated that extracellular collagen fibrillogenesis is a valid and specific target to reduce collagen-rich scar buildup. Our previous studies showed that a rationally designed antibody that binds the C-terminal telopeptide of the α2(I) chain involved in the aggregation of collagen molecules limits fibril assembly in vitro and reduces scar formation in vivo. Here, we have utilized a clinically relevant arthrofibrosis model to study the broad mechanisms of the anti-scarring activity of this antibody. Moreover, we analyzed the effects of targeting collagen fibril formation on the quality of healed joint tissues, including the posterior capsule, patellar tendon, and subchondral bone. Our results show that blocking collagen fibrillogenesis not only reduces collagen content in the scar, but also accelerates the remodeling of healing tissues and changes the collagen fibrils' cross-linking. In total, this study demonstrated that targeting collagen fibrillogenesis to limit arthrofibrosis affects neither the quality of healing of the joint tissues nor disturbs vital tissues and organs., Competing Interests: We declare that Drs. Fertala and Steplewski are co-inventors of the antibody used in this study. The antibody’s sequence is protected by the patent entitled: “Engineered antibody for inhibition of fibrosis,” US Patent 9,777,055; 10,501,533.

Rheumatoid arthritis (RA) is a debilitating autoimmune disease of unknown cause, characterized by infiltration and accumulation of activated immune cells in the synovial joints where cartilage and bone destructions occur. Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) was shown to be involved in the regulation of MDSC differentiation. The purpose of the present study was to investigate the effect of inhibition of SHIP1 on the expansion of MDSCs in RA using a collagen-induced inflammatory arthritis (CIA) mouse model. In DBA/1 mice, treatment with a small molecule-specific SHIP1 inhibitor 3α-aminocholestane (3AC) induced a marked expansion of MDSCs in vivo. Both pretreatment with 3AC of DBA/1 mice prior to CIA induction and intervention with 3AC during CIA progression significantly reduced disease incidence and severity. Adoptive transfer of MDSCs isolated from 3AC-treated mice, but not naïve MDSCs from normal mice, into CIA mice significantly reduced disease incidence and severity, indicating that the 3AC-induced MDSCs were the cellular mediators of the observed amelioration of the disease. In conclusion, inhibition of SHIP1 expands MDSCs in vivo and attenuates development of CIA in mice. Small molecule-specific inhibition of SHIP1 may therefore offer therapeutic benefit to patients with RA and other autoimmune diseases.

Background: Frozen shoulders (FS) is a major clinical concern, where chronic synovial inflammation, abnormal angiogenesis, and fibrosis represent the critical pathologies in the glenohumeral capsule. However, no pharmacotherapy has been introduced to treat this pathology. Tetrandrine (TET) has been proposed as a treatment for many diseases due to its strong anti-inflammatory, anti-angiogenic, and anti-fibrotic effects., Purpose: To study the anti-inflammatory, anti-angiogenic, and anti-fibrotic effects of TET on FS, and identify whether TET can prevent the development of FS in rats., Study Design: A controlled laboratory study., Methods: Forty-eight male Sprague-Dawley (SD) rats were randomly divided into control, TET, and FS groups. The TET group was intraperitoneally injected with TET every 2 days. TET and saline treatment were started on the day of FS surgery. After 8 weeks, the animals were sacrificed, and samples were collected for X-ray examination, glenohumeral range of motion (ROM) evaluation, histology and immunohistochemistry analysis, transmission electron microscopy (TEM) observation, and profibrogenic factors as well as proinflammatory cytokines measurements., Results: No significant difference in shoulder ROM was observed between the TET and control groups, but a significant difference was noted between these groups and the FS group (P < 0.01). Immunohistochemical staining showed no abnormal angiogenesis or fibrosis in the TET group or the control group. However, significant angiogenesis, collagen remodeling, and fibrosis were observed in the FS group, and the expression and proportion of type I and type III collagen in the FS group were significantly higher than those in the TET group or the control group (P < 0.01). TEM observation showed that TET protected the ultrastructure of collagen fibrous reticular arrangement of the articular capsule and prevented the formation of scar-like fibrotic structures, which are unique to FS. The significantly increased expression of Smad7 and the suppressed expression of Smad 2 in the TET group compared with that of the FS group indicated that TET also significantly inhibited the TGF-β1 intracellular signal pathway. The expression of profibrogenic factors and proinflammatory cytokines in the TET group and the control group was significantly lower than that in the TET group (P < 0.01)., Conclusion: The results demonstrated that TET protected the normal reticular structure of the capsule during the freezing period and prevented the development of FS by inhibiting inflammation, angiogenesis, and fibrosis in a rat FS model., Clinical Relevance: TET may be a safe and effective clinical medication for preventing and treating FS., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: To analyze biopsy samples from the subscapularis tendon and from the joint capsule from male patients with subacromial impingement syndrome and compare them with samples from male patients with post-traumatic recurrent shoulder instability, to detect increased inflammatory activity that might be present inside the humeroscapular joint., Methods: Twenty male patients scheduled for surgery for either subacromial decompression or Bankart reconstruction were included. Four biopsies from each patient were obtained during surgery from the capsule and the subscapularis tendon. Each specimen was analyzed for TNF-α, IL-6, CD-3 and CD-72. Multiplex fluorescence immunohistochemistry was performed on histological samples from the capsule and tendon to demonstrate the level of inflammatory markers. Fluorescence microscope images were acquired using an automated scanning system. On each slide, the number of pixels was registered and used in the analyses., Results: The subacromial impingement syndrome group comprised eight patients, median age 53 (45-74) years, while the instability group 12, median age 27 (22-48) years (p < 0.00001). The amount of IL-6 and TNF-α was significantly higher in the subscapularis tendon of the patients with subacromial impingement syndrome compared with instability patients (p = 0.0015 and p = 0.0008 respectively). In the capsular samples, significantly higher amount of TNF-α and CD-72 was found in patients with subacromial impingement syndrome compared with instability patients (p < 0.0001 for both). On the other hand, the amount of CD-3 was significantly higher in the instability group (p = 0.0013)., Conclusions: This study provides evidence that an extended inflammatory process is present, not only in the subacromial bursa but also in the glenohumeral joint in patients with subacromial impingement syndrome., Level of Evidence: Level III., Clinical Relevance: To develop a treatment targeted towards intra-articular inflammatory cytokines appears appealing.

Effective treatment of osteoarthritis (OA) remains a huge clinical challenge despite major research efforts. Different tissues and cell-types within the joint contribute to disease pathogenesis, and there is great heterogeneity between patients in terms of clinical features, genetic characteristics and responses to treatment. Inflammation and the most abundant immune cell type within the joint, macrophages, have now been recognised as possible players in disease development and progression. Here we discuss recent findings on the involvement of synovial inflammation and particularly the role of synovial macrophages in OA pathogenesis. Understanding macrophage involvement may hold the key for improved OA treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Thomson and Hilkens.)

Background: Capsulitis leads to the release of inflammatory mediators in the joint, causing capsular fibrosis and osteoarthritis (OA). Strain elastosonography (SE) measures the elasticity of tissue by evaluating its strain in operator-dependent deformation. The aims of the study were to assess the feasibility, repeatability, and reproducibility of SE for imaging the distal attachment of the joint capsule (DJC) of metacarpophalangeal joints in sound horses (Group S) and in horses with metacarpophalangeal OA (Group P) and to evaluate differences in the elastosonographic patterns of these horses. After a whole lameness examination, fore fetlock DJCs were assigned to Group S and Group P and were thereafter examined by two operators using SE. Qualitative (i.e., colour grading score) and semi-quantitative (i.e., elasticity index (EI) and strain ratio (SR)) methods were used to evaluate the elastograms. The inter-rater reliability (IRR), intraclass correlation coefficient (intra-CC) and interclass correlation coefficient (inter-CC) were used to compare colour grading scores and the repeatability and reproducibility of EI and SR outcomes. The same parameters were compared between groups. P < 0.05 indicated a significant finding., Results: Forty-one horses were included: 11 were in Group S and 30 were in Group P (16 with bilateral OA, 8 with left OA and 6 with right OA). IRR outcomes ranged from good to excellent. For transverse and longitudinal ultrasound scans, the colour grading score of Group S was significantly higher than the metacarpophalangeal DJCs of Group P. Both Inter-CC and intra-CC were higher in Group S than in Group P, with values always > 0.8. Significative differences in EI and SR were detected between groups and between Group S and the affected limb of Group P; values were lower in Group S than in Group P., Conclusions: SE can be a useful technique for evaluating DJCs, with good repeatability and reproducibility. DJCs appear softer in sound horses.

Knee joint contracture is often induced by anterior cruciate ligament reconstruction (ACLR). However, the temporal and spatial arthrofibrotic changes following inflammatory events, which occur in parallel with the formation of joint contractures after ACLR, are unknown. This study aimed to reveal: (a) time-dependent changes in myogenic and arthrogenic contractures; and (b) the process of arthrofibrosis development after ACLR. ACLR was performed on knees of rats unilaterally. Passive ranges of motions (ROMs) before and after myotomy, as well as inflammatory and fibrotic reactions, were examined before and after the surgery at various periods up to 56 days. Both ROMs before and after myotomy exhibited their lowest value on day 7 and increased thereafter in a time-dependent manner; nevertheless, significant restrictions remained by day 56. Myotomy partially increased ROMs at all time points, indicating contribution of the myogenic component to ACLR-induced contracture. Inflammatory and fibrotic reactions peaked on day 7. Arthrofibrosis, characterized by the thickening of the joint capsule and the shortening of the synovial length, was established by day 7 and was not completely resolved by day 56. Our results indicate that: (a) both myogenic and arthrogenic contractures generated through ACLR develop maximally by day 7 after surgery and subside thereafter, but persist at least until day 56; and (b) arthrofibrosis is established by day 7 after surgery and is not completely resolved by day 56. These findings suggest that treatment and intervention for preventing joint contracture after ACLR should be performed within the first 7 days after surgery., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Joint capsule fibrosis caused by excessive inflammation results in post-traumatic joint contracture (PTJC). Transforming growth factor (TGF)-β1 plays a key role in PTJC by regulating fibroblast functions, however, cytokine-induced TGF-β1 expression in specific cell types remains poorly characterized. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in inflammation- and fibrosis-associated pathophysiology. In this study, we investigated whether MIF can facilitate TGF-β1 production from fibroblasts and regulate joint capsule fibrosis following PTJC. Our data demonstrated that MIF and TGF-β1 significantly increased in fibroblasts of injured rat posterior joint capsules. Treatment the lesion sites with MIF inhibitor 4-Iodo-6-phenylpyrimidine (4-IPP) reduced TGF-β1 production and relieved joint capsule inflammation and fibrosis. In vitro , MIF facilitated TGF-β1 expression in primary joint capsule fibroblasts by activating mitogen-activated protein kinase (MAPK) (P38, ERK) signaling through coupling with membrane surface receptor CD74, which in turn affected fibroblast functions and promoted MIF production. Our results reveal a novel function of trauma-induced MIF in the occurrence and development of joint capsule fibrosis. Further investigation of the underlying mechanism may provide potential therapeutic targets for PTJC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The surgical treatment of femoroacetabular impingement has been shown to have successful early and mid-term clinical outcomes. Despite these favorable clinical outcomes that have been published in the literature, there is a subgroup of patients that present with continued or recurrent symptoms after surgical treatment. Not only has there been an increase in the number of hip arthroscopy procedures, but also there has been a corresponding increase in the number of revision hip arthroscopy and hip preservation surgeries. Previous studies have reported residual deformity to be the most common reason for revision hip arthroscopy. However, chondral, labral, and capsular considerations also are important when addressing patients not only in the primary but also, the revision setting. In this review, we outline the evaluation and treatment of the patient that presents with continued hip and groin pain after undergoing a hip., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Joint capsule fibrosis caused by excessive inflammation leading to post-traumatic joint contracture (PTJC). Fibroblasts trigger inflammation under the challenge of various proinflammatory cytokines. Macrophage migration inhibitory factor (MIF) is a prominent proinflammatory cytokine involved in inflammation- and fibrosis-associated pathophysiology, we investigated the role of MIF in PTJC., Methods: Using rat PTJC model and fibroblast inflammation model, we detected MIF expression in posterior joint capsule. Primary joint capsule fibroblasts (JFs) were used to investigate the effects of MIF on cell proliferation, migration and proinflammatory cytokines production. The mechanism of JF-mediated events was evaluated by qRT-PCR, western blot and immunoprecipitation. We screened the mRNA expression profile to identify gene candidates that mediate the effect of MIF on JFs., Results: MIF increased in posterior joint capsule following PTJC and co-localized with fibroblasts. Injection of MIF inhibitor significantly suppressed joint capsule inflammation and fibrosis. In vitro , MIF promoted JF proliferation, migration, and inflammation by regulating mitogen-activated protein kinase/nuclear factor-κB pathway through coupling with CD74. Transcriptome analysis revealed that lipid metabolism-related factors Pla2g2a, Angptl4, and Sgpp2, downstream of MIF/CD74, were potentially implicated in JF inflammation., Conclusion: MIF/CD74 axis elicited JF inflammation and may provide new therapeutic targets for joint capsule fibrosis in PTJC.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concern was raised about the reliability of the Western blot results in Figs. 1C and 7B, which appear to have the same eyebrow shaped phenotype as many other publications tabulated here (https://docs.google.com/spreadsheets/d/149EjFXVxpwkBXYJOnOHb6RhAqT4a2llhj9LM60MBffM/edit#gid=0). The journal requested the corresponding author comment on these concerns and provide the raw data. However the authors were not able to satisfactorily fulfil this request and therefore the Editor-in-Chief decided to retract the article., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Range of motion adaptations in the shoulders of overhead throwing athletes have been reported, but knowledge about the development of soft-tissue adaptations is limited. The purpose of this study was to investigate differences in posterior shoulder capsule thickness and internal rotation between the throwing and non-throwing shoulder., Methods: On the basis of the sample size calculation, we assessed 63 youth elite handball players (33 boys and 30 girls, mean age: 13.6 ± 0.9 years) for glenohumeral internal and external rotational range of motion, humeral retrotorsion, and posterior capsule thickness (PCT) with a manual goniometer and a portable ultrasound device and calculated sports-specific differences between the throwing and non-throwing shoulder as well as correlations with PCT., Results: Youth handball players showed side-to-side differences in internal rotation, external rotation, and humeral retrotorsion between the throwing and non-throwing shoulder. Posterior shoulder capsules were 1.21 times thicker (95% confidence interval: 1.1-1.3) in the throwing shoulder than in the non-throwing shoulder (1.3 ± 0.3 mm vs. 1.2 ± 0.2 mm, P < .0001). Loss of internal rotation did not correlate with PCT., Conclusions: In youth elite handball athletes, posterior shoulder tightness and subsequent sports-specific loss of internal rotation in the throwing shoulder are not related to PCT. Thus, in this age class, other (soft-tissue) factors must be responsible for this condition., (Copyright © 2020 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

The human immune system has evolved to recognize and eradicate pathogens, a process that is known as "host defense". If, however, the immune system does not work properly, it can mistakenly attack the body's own tissues and induce autoimmune diseases. Rheumatoid arthritis (RA) is such an autoimmune disease in which the synovial joints are predominately attacked by the immune system. Moreover, RA is associated with bone destruction and joint deformity. Although biologic agents have propelled RA treatment forward dramatically over the past 30 years, a considerable number of patients with RA still experience progressive bone damage and joint disability. That is to be expected since current RA therapies are all intended to halt inflammation but not to alleviate bone destruction. A better understanding of bone erosions is crucial to developing a novel strategy to treat RA-associated erosions. This review provides insights into RA-associated bone destruction and perspectives for future clinical interventions.

Joint contracture (also known as arthrofibrosis) is a fibrotic joint disorder characterized by excessive collagen production to form fibrotic scar tissue and adhesions within joint capsules. This can severely affect day-to-day activities and quality of life because of a restricted range of motion in affected joints. The precise pathogenic mechanism underlying joint contractures is not fully understood. Lumican belongs to the class II small leucine-rich repeat proteoglycan superfamily, which makes up collagen fibrils in the extracellular matrix. Lumican is ubiquitously expressed in the skin, liver, heart, uterus and articular cartilage and has reported roles in cell migration, proliferation, angiogenesis and Toll-like receptor 4 signaling. Previous research has suggested that lumican is involved in the pathogenesis of several fibrotic diseases. Because joint contracture resembles a fibrotic disease, we aimed to investigate the role of lumican in the development of joint contracture in vitro. Here, we showed that protein levels were up-regulated in the fibrotic joint capsule versus control. We observed that lumican significantly enhanced the proliferation, migration and fibroblast-myofibroblast transition of synovial fibroblasts. Moreover, lumican led to increased transcription of alpha-smooth muscle actin, matrix metallopeptidase 9, Collagen I, plasminogen activator inhibitor 1 and transforming growth factor-β in vitro. Lumican treatment promoted collagen lattice contraction in a dose-dependent manner as early as 24 h after treatment. Thus, our studies reveal that lumican could promote fibroblast-myofibroblast transition and joint contracture., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Background : The pathophysiology of idiopathic frozen shoulder (FS) remains poorly described. There is a lack of differentiation between idiopathic and secondary cause. The aim of this systematic review was to summarize the evidence regarding the pathophysiology of idiopathic FS on a molecular level and emphasize the clinical relevance. Methods : A database search of Medline, EMBASE and Cochrane Central Register of Controlled Trials from inception to April 2018 was performed. Participants who underwent previous injections or surgeries were excluded. A thorough selection and quality assessment process using the Cochrane Risk of Bias assessment tool and the Joanna Briggs Institute Critical Appraisal Checklist was conducted by two reviewers independently. Results : A total of 15 studies analyzing 333 study subjects were included. Twelve studies evaluated capsular tissue and three studies investigated blood samples. The tissue samples revealed increased expression of various inflammatory cytokines including interleukins, cyclooxygenase and tumor necrosis factor. Several types of acid-sensing ion channels (ASIC1 and ASIC3) were associated with disturbed neurogenesis and melatonin-regulated pain mechanism. The blood samples showed prevalence of specific interleukin and metalloproteinase genotypes. A decreased matrix metalloproteinase/tissue inhibitor of metalloproteinase ratio was found both in tissue and blood. Conclusion : The findings indicate an abnormal local neurogenesis with possible regulation through melatonin. The disturbance in remodeling of the extracellular matrix and in collagen translation, together with a persistent inflammation and an impaired healing, all interact in the process that leads to persistent fibrosis. There is global fibroplasia with localized anterior capsule contracture.

Background: Scapulohumeral periarthritis (SP) is a very common painful shoulder disorder. Several systematic reviews (SRs) and meta-analyses have reported the effectiveness of acupuncture for patients with SP. However, the evidence has not been systematically synthesized. This overview aims to map, synthesize, and assess the reliability of evidence generated from these SRs and meta-analyses of acupuncture for SP., Methods: We will electronically search the following databases for literature, regardless of publication status and language: the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; China National Knowledge Infrastructure (CNKI); Chinese Biomedical Literature Database (CBM); Chinese Scientific Journal Database (VIPdatabase); and Wan-Fang Database. In order to ensure the comprehensiveness and accuracy of the literature retrieval, we will combine the Suggestions of evidence-based medicine experts with the actual situation in the literature retrieval process to formulate the retrieval strategy, and make corresponding records to find the most appropriate retrieval strategy. The reference lists and the citation lists of studies meeting the inclusion criteria and relevant SRs will also be searched to identify further studies for inclusion. Before this review completed, the two reviewers will conduct the searching once again to ensure the latest studies could be included., Ethics and Dissemination: Ethical approval is not required for overviews. We plan to publish results in peer-reviewed journals and present at international and national academic, clinical, and patient conferences., Results: The results will be published in a peer-reviewed journal., Conclusion: This overview will provide comprehensive evidence of acupuncture for patients with SP., Inplasy Registration Number: INPLASY202060020.

Background: While multiple in vitro studies examined mesenchymal stromal cells (MSCs) derived from bone marrow or hyaline cartilage, there is little to no data about the presence of MSCs in the joint capsule or the ligamentum capitis femoris (LCF) of the hip joint. Therefore, this in vitro study examined the presence and differentiation potential of MSCs isolated from the bone marrow, arthritic hyaline cartilage, the LCF and full-thickness samples of the anterior joint capsule of the hip joint., Methods: MSCs were isolated and multiplied in adherent monolayer cell cultures. Osteogenesis and adipogenesis were induced in monolayer cell cultures for 21 days using a differentiation medium containing specific growth factors, while chondrogenesis in the presence of TGF-ß1 was performed using pellet-culture for 27 days. Control cultures were maintained for comparison over the same duration of time. The differentiation process was analyzed using histological and immunohistochemical stainings as well as semiquantitative RT-PCR for measuring the mean expression levels of tissue-specific genes., Results: This in vitro research showed that the isolated cells from all four donor tissues grew plastic-adherent and showed similar adipogenic and osteogenic differentiation capacity as proven by the histological detection of lipid droplets or deposits of extracellular calcium and collagen type I. After 27 days of chondrogenesis proteoglycans accumulated in the differentiated MSC-pellets from all donor tissues. Immunohistochemical staining revealed vast amounts of collagen type II in all differentiated MSC-pellets, except for those from the LCF. Interestingly, all differentiated MSCs still showed a clear increase in mean expression of adipogenic, osteogenic and chondrogenic marker genes. In addition, the examination of an exemplary selected donor sample revealed that cells from all four donor tissues were clearly positive for the surface markers CD44, CD73, CD90 and CD105 by flow cytometric analysis., Conclusions: This study proved the presence of MSC-like cells in all four examined donor tissues of the hip joint. No significant differences were observed during osteogenic or adipogenic differentiation depending on the source of MSCs used. Further research is necessary to fully determine the tripotent differentiation potential of cells isolated from the LCF and capsule tissue of the hip joint.

To date, we could find no study concerning the relationship between mechanoreceptors in the joint capsule of the first metatarsophalangeal joint and hallux valgus deformity. We aimed to investigate the presence of mechanoreceptors in samples obtained from the first metatarsophalangeal joint capsules of patients with hallux valgus deformity to improve our understanding of the clinical and histopathological features of the disease. Samples were taken from the first metatarsophalangeal joint capsules of 13 fresh-frozen cadavers with normal anatomy (controls) and 29 patients undergoing surgery for hallux valgus (cases). For light microscopy, excised specimens were fixed in 10% formaldehyde and processed for routine histopathological investigation. All samples were dehydrated in a series of ethanol, cleared in xylene, and embedded in paraffin. Orientation of collagen fibers was determined on Masson's trichrome-stained sections, and mechanoreceptors were evaluated on S-100-immunostained sections. In the sections stained with Masson's trichrome, the orientation of collagen fibers was regular in the control group. However, coarse and disoriented collagen bundles were observed in the hallux valgus cases (P ≤ .05). S-100 immunostaining was positive in the sections of both the cases and controls. Finally, free nerve endings were more abundant in the samples obtained from the capsules of hallux valgus cases than from the control group (P ≤ .05). An increase in the number of free nerve endings within the capsules of the first metatarsophalangeal joints in feet with hallux valgus deformity might have a role in the development of clinically relevant joint pain and instability., (Copyright © 2020 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Shortly after joint remobilization, inflammation is induced in the joint and aggravates joint contracture via subsequent fibrosis. However, the mechanisms involved in remobilization-induced inflammation are not yet fully understood. We hypothesized that joint immobilization followed by remobilization induces hypoxia/reoxygenation, initiating inflammatory reactions through nitric oxide (NO) production via NO synthase 2 (NOS2). This study aimed to investigate whether: 1) administration of the NOS inhibitor L-NG-nitroarginine methyl ester (l-NAME) can attenuate remobilization-induced joint inflammation; and 2) hypoxia/reoxygenation is induced by joint immobilization and followed by remobilization. Unilateral knee joints of rats were immobilized using external fixators for three weeks. After removal of the fixation device, knees were allowed to move freely for one day (remobilization) with or without l-NAME administration. Without l-NAME administration, inflammatory reactions including joint swelling and inflammatory cell infiltration, edema, and upregulation of inflammatory mediator genes in the joint capsule were detected following upregulation of the NOS2 gene after remobilization. These remobilization-induced inflammatory reactions were partially attenuated by administration of l-NAME. Therefore, NOS2/NO elevation has potential as a novel treatment for remobilization-induced joint inflammation. Gene expression of the hypoxia marker hypoxia inducible factor-1α was upregulated after one day of remobilization, rather than after immobilization. These results suggest that upregulation of NOS2 by remobilization might be not due to hypoxia/reoxygenation., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Joint stiffness due to fibrosis/capsule contracture is a seriously disabling complication of articular injury that surgical interventions often fail to completely resolve. Fibrosis/contracture is associated with the abnormal persistence of myofibroblasts, which over-produce and contract collagen matrices. We hypothesized that intra-articular therapy with drugs targeting myofibroblast survival (sulfasalazine), or collagen production (β-aminopropionitrile and cis-hydroxyproline), would reduce joint stiffness in a rabbit model of fibrosis/contracture. Drugs were encapsulated in poly[lactic-co-glycolic] acid pellets and implanted in joints after fibrosis/contracture induction. Capsule α-smooth muscle actin (α-SMA) expression and intimal thickness were evaluated by immunohistochemistry and histomorphometry, respectively. Joint stiffness was quantified by flexion-extension testing. Drawer tests were employed to determine if the drugs induced cruciate ligament laxity. Joint capsule fibroblasts were tested in vitro for contractile activity and α-SMA expression. Stiffness in immobilized joints treated with blank pellets (control) was significantly higher than in non-immobilized, untreated joints (normal) (p = 0.0008), and higher than in immobilized joints treated with sulfasalazine (p = 0.0065). None of the drugs caused significant cruciate ligament laxity. Intimal thickness was significantly lower than control in the normal and sulfasalazine-treated groups (p = 0.010 and 0.025, respectively). Contractile activity in the cells from controls was significantly increased versus normal (p = 0.001). Sulfasalazine and β-aminopropionitrile significantly inhibited this effect (p = 0.005 and 0.0006, respectively). α-SMA expression was significantly higher in control versus normal (p = 0.0021) and versus sulfasalazine (p = 0.0007). These findings support the conclusion that sulfasalazine reduced stiffness by clearing myofibroblasts from fibrotic joints. Statement of clinical significance: The results provide proof-of-concept that established joint stiffness can be resolved non-surgically. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:629-638, 2020., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

This study aimed to develop a rabbit model of knee contracture in extension and investigate the natural history of motion loss and time-dependent changes in the joint capsule after immobilization. We immobilized the unilateral knee joints of 32 rabbits by maintaining the knee joint in a plaster cast at full extension. Eight rabbits were euthanized at 2, 4, 6, and 8 weeks after casting, respectively, and the lower extremities were disarticulated at the hip joint. Eight control group rabbits that did not undergo immobilization were also examined. We assessed the progression of joint contracture by measuring the joint range of motion, evaluating the histologic alteration of the capsule, and assessing the mRNA levels of transforming growth factor β1 (TGF-β1) in the anterior and posterior joint capsules. After 2 weeks of joint immobilization, the knee joint range of motion was limited, the synovial membrane of the suprapatellar and posterior joint capsules was thickened, the collagen deposition was increased, and the mRNA levels of TGF-β1 were elevated in the anterior and posterior joint capsules. These changes progressed rapidly until 6 weeks of immobilization and may advance slowly after 6 weeks. Joint contracture developed at the early stage of immobilization and progressed over time. The changes in the anterior and posterior joint capsules after joint immobilization may contribute to the limitation in flexion. The elevated mRNA expression of TGF-β1 may be related to joint capsule fibrosis and may be one of the causes of joint contracture., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objectives: This study aims to histologically examine the joint capsule and synovium to determine the correlation between histopathological findings and postoperative clinical outcomes in patients with isolated type II superior labrum anterior posterior (SLAP) lesions., Patients and Methods: Thirty-eight patients (24 males, 14 females; mean age 53.2±6.6 years; range, 45 to 67 years) who underwent arthroscopic treatment of type II SLAP lesions between June 2017 and September 2018 were evaluated prospectively. Visual analog scale (VAS), Simple Shoulder Test (SST), and American Shoulder and Elbow Surgeons (ASES) scores of all patients were recorded preoperatively, and at 6th and 12th months postoperatively. Biceps tenotomy was applied as arthroscopic surgical treatment in all patients. Biopsy materials obtained from rotator interval joint capsule and synovium during the arthroscopy were evaluated histopathologically. The density of the vessels in the specimens was defined as low, medium, and high by the pathologist. The patients with medium or low vessel density in specimens were group 1 (n=14) and those with high vessel density group 2 (n=24)., Results: In group 2, preoperative VAS score was significantly higher. There was no difference between the scores of the groups except for the sixth month SST score which was significantly higher in group 1. Histopathological evaluation revealed that the number of lymphocytes, fibroblasts, mast cells, myofibroblast, synovial lining cells, macrophages, and amount of collagen in connective tissue were significantly higher in group 2. In five patients of group 2, the rehabilitation program was interrupted due to pain and difficulty in gaining a range of motion during the first four weeks postoperatively. Four of these patients recovered with medication and long-duration physiotherapy. Shoulder stiffness developed in one patient who required arthroscopic release and further rehabilitation., Conclusion: There is a correlation between histopathological findings of joint capsule and synovium, and postoperative clinical outcomes and treatment in patients with isolated type II SLAP lesions. Almost 20% of patients who had pathologic histological findings in joint capsule and synovium needed pain control and long-duration rehabilitation program after arthroscopic surgery for better shoulder function recovery and prevention of shoulder stiffness.

Background: Assessment of a painful or stiff shoulder arthroplasty can be challenging. The cause of pain can sometimes be easily identified. However, some patients have normal levels of inflammatory markers, normal plain films, and no clinical signs to indicate a diagnosis. Indolent organisms may not raise blood marker levels or result in obvious radiologic findings such as loosening. We report the utility of performing arthroscopy in these patients for a diagnostic advantage., Methods: We retrospectively reviewed the health records of all patients who underwent diagnostic shoulder arthroscopy over a 3-year period. Patients were included if they were aged 18 years or older, had undergone previous arthroplasty surgery, and had symptoms of shoulder pain or stiffness. Patients were excluded if they had any traditional symptoms of infection or had a raised serum white cell count or C-reactive protein level prior to diagnostic arthroscopy., Results: Fourteen patients met the initial inclusion criteria. The mean interval between index surgery and arthroscopic evaluation was 65.4 months (standard deviation, 58 months; range, 17-192 months). Arthroscopic biopsy specimens returned positive culture results in 3 patients (21%). Rotator cuff tears were noted in 8 patients (57%). Capsular contraction requiring release was noted in 2 patients (10%). In all patients, the diagnostic arthroscopy directed the next stage of management., Conclusions: Diagnostic arthroscopy allows a full assessment of implants, the rotator cuff, the native articular surfaces, and scar tissue, as well as biopsy specimens to be obtained for indolent infection, in patients considering revision arthroplasty surgery. This allows a more informative consent process for patients, directs surgical management, and on occasion, allows for therapeutic intervention in a painful or stiff shoulder arthroplasty., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Synovial plicae are vestigial folds of synovium in a joint, most widely recognized in the knee and also in the elbow and hip joints. The most commonly shared theory on the origin of plicae is that they are the remnants of the membranes that divide the synovial cavitations during normal joint development. Synovial folds do not generally cause any symptoms. However, they can become inflamed, thickened, fibrosed, and also impinged in the joint, leading to mechanical symptoms and chondral damage. This article presents an overview of the embryological origin of plicae, their anatomy, pathologies, and appearances on imaging. We also discuss the lesser known plicae in various other areas., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Patients with late-stage Kellgren-Lawrence knee osteoarthritis received a single intra-articular injection of 1, 10, or 50 million bone marrow mesenchymal stromal cells (BM-MSCs) in a phase I/IIa trial to assess safety and efficacy using a broad toolset of analytical methods. Besides safety, outcomes included patient-reported outcome measures (PROMs): Knee Injury and Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); contrast-enhanced magnetic resonance imaging (MRI) for cartilage morphology (Whole Organ MRI Scores [WORMS]), collagen content (T2 scores), and synovitis; and inflammation and cartilage turnover biomarkers, all over 12 months. BM-MSCs were characterized by a panel of anti-inflammatory markers to predict clinical efficacy. There were no serious adverse events, although four patients had minor, transient adverse events. There were significant overall improvements in KOOS pain, symptoms, quality of life, and WOMAC stiffness relative to baseline; the 50 million dose achieved clinically relevant improvements across most PROMs. WORMS and T2 scores did not change relative to baseline. However, cartilage catabolic biomarkers and MRI synovitis were significantly lower at higher doses. Pro-inflammatory monocytes/macrophages and interleukin 12 levels decreased in the synovial fluid after MSC injection. The panel of BM-MSC anti-inflammatory markers was strongly predictive of PROMs over 12 months. Autologous BM-MSCs are safe and result in significant improvements in PROMs at 12 months. Our analytical tools provide important insights into BM-MSC dosing and BM-MSC reduction of synovial inflammation and cartilage degradation and provide a highly predictive donor selection criterion that will be critical in translating MSC therapy for osteoarthritis. Stem Cells Translational Medicine 2019;8:746&757., (© 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Background: After a trauma, exuberant tissue healing with fibrosis of the joint capsule can lead to posttraumatic joint stiffness (PTJS). Losartan and atorvastatin have both shown their antifibrotic effects in different organ systems., Objective: The purpose of this study was the evaluation of the influence of losartan and atorvastatin on the early development of joint contracture. In addition to joint angles, the change in myofibroblast numbers and the distribution of bone sialoprotein (BSP) were assessed., Study Design and Methods: In this randomized and blinded experimental study with 24 rats, losartan and atorvastatin were compared to a placebo. After an initial joint injury, rat knees were immobilized with a Kirschner wire. Rats received either losartan, atorvastatin or a placebo orally daily. After 14 days, joint angle measurements and histological assessments were performed., Results: Losartan increased the length of the inferior joint capsule. Joint angle and other capsule length measurements did not reveal significant differences between both drugs and the placebo. At cellular level both losartan and atorvastatin reduced the total number of myofibroblasts (losartan: 191±77, atorvastatin: 98±58, placebo: 319±113 per counting field, p <0.01) and the percentage area of myofibroblasts (losartan: 2.8±1.8% [ p <0.05], atorvastatin: 2.5±1.7% [ p <0.01], vs control [6.4±4%], respectively). BSP was detectable in equivalent amounts in the joint capsules of all groups with only a trend toward a reduction of the BSP-stained area by atorvastatin., Conclusion: Both atorvastatin and losartan reduced the number of myofibroblasts in the posterior knee joint capsule of rat knees 2 weeks after trauma and losartan increased the length of the inferior joint capsule. However, these changes at the cellular level did not translate an increase in range of motion of the rats´ knee joints during early contracture development., Competing Interests: Dr Andreas Baranowski reports grants from the Johannes Gutenberg-University Mainz and the German Society of Shoulder and Elbow Surgery (DVSE), during the conduct of the study. Dr Anja Klein reports grants from the German Society of Shoulder and Elbow Surgery (DVSE) and Inneruniversitäre Forschungsförderung Stufe I, during the conduct of the study. The authors report no other conflicts of interest in this work.

Background: Although frozen shoulder (FS) is a common shoulder disorder, its pathogenesis is not yet determined. The function of matrix metalloproteinases (MMPs) is related to extracellular matrix remodeling. The purposes of this study were to investigate the pattern of sequential expression of MMPs in a rat model of shoulder contracture and to compare the expression of MMPs in the joint capsule between patients with FS and a control group., Methods: We obtained joint capsules from rats immobilized by molding plaster (a shoulder contracture model) at baseline, 3 days, 1 week, and 3 weeks (4 rats per time point; 16 rats in total). The expression of the inflammatory cytokine interleukin 6 (IL-6), MMP-2, and MMP-9 was examined by immunohistochemistry. We also obtained joint capsules from 21 patients with FS and 13 control patients with instability to quantify the expression levels of MMP-2 and MMP-9 by immunohistochemistry., Results: In the rat model, IL-6 and MMP-9 tended to be overexpressed in the joint capsule at 3 days and 1 week and MMP-2 at 3 days, 1 week, and 3 weeks. MMP-2 and MMP-9 were significantly overexpressed in the joint capsules of the patients with FS compared with those of control patients., Conclusion: The results from both human and animal studies suggest the involvement of MMP-2 and MMP-9 in the development of FS. Animal study showed that the sequential expression of IL-6 and MMPs may be associated with fibrosis of the joint capsule., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Objective: To compare inferior capsular redundancy by using magnetic resonance arthrography (MRA) images in patients with multidirectional instability (MDI) of the shoulder and control subjects without instability and thereby develop a screening method to identify the presence of shoulder MDI., Materials and Methods: The MRA images of patients with MDI of the shoulder (n = 65, 57 men, 8 women; mean age, 24.5 years; age range, 18-42 years) treated over an eight-year period were retrospectively reviewed; a control group (n = 65, 57 men, 8 women; mean age, 27.4 years; age range, 18-45 years) without instability was also selected. The inferior capsular redundancy was measured using a new method we named the glenocapsular (GC) ratio method. MRA images of both groups were randomly mixed together, and two orthopedic surgeon reviewers measured the cross-sectional areas (CSAs) and sagittal capsule-head ratios on oblique sagittal images, as well as the axial capsule-head ratios on axial images and GC ratios on oblique coronal images., Results: The CSAs and GC ratios were significantly higher in patients than in controls (both, p < 0.001); however, the sagittal capsule-head ratios and axial capsule-head ratios were not significantly different ( p = 0.317, p = 0.053, respectively). In addition, GC ratios determined the presence of MDI more sensitively and specifically than did CSAs. A GC ratio of > 1.42 was found to be most suggestive of MDI of the shoulder, owing to its high sensitivity (92.3%) and specificity (89.2%)., Conclusion: GC ratio can be easily measured and used to accurately screen for MDI of the shoulder., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2019 The Korean Society of Radiology.)

Cadherins are homophilic cell-to-cell adhesion molecules that help cells respond to environmental changes. Newly formed cadherin junctions are associated with increased cell phosphorylation, but the pathways driving this signaling response are largely unknown. Since cadherins have no intrinsic signaling activity, this phosphorylation must occur through interactions with other signaling molecules. We previously reported that cadherin-11 engagement activates joint synovial fibroblasts, promoting inflammatory and degradative pathways important in rheumatoid arthritis (RA) pathogenesis. Our objective in this study was to discover interacting partners that mediate cadherin-11 signaling. Protein array screening showed that cadherin-11 extracellular binding domains linked to an Fc domain (cad11Fc) induced platelet-derived growth factor (PDGFR)-α phosphorylation in synovial fibroblasts and glioblastoma cells. PDGFRs are growth factor receptor tyrosine kinases that promote cell proliferation, survival, and migration in mesodermally derived cells. Increased PDGFR activity is implicated in RA pathology and associates with poor prognosis in several cancers, including sarcoma and glioblastoma. PDGFRα activation by cadherin-11 signaling promoted fibroblast proliferation, a signaling pathway independent from cadherin-11-stimulated IL-6 or matrix metalloproteinase (MMP)-3 release. PDGFRα phosphorylation mediated most of the cad11Fc-induced phosphatidyl-3-kinase (PI3K)/Akt activation, but only part of the mitogen-activated protein kinase (MAPK) response. PDGFRα-dependent signaling did not require cell cadherin-11 expression. Rather, cad11Fc immunoprecipitated PDGFRα, indicating a direct interaction between cadherin-11 and PDGFRα extracellular domains. This study is the first to report an interaction between cadherin-11 and PDGFRα and adds to our growing understanding that cadherin-growth factor receptor interactions help balance the interplay between tissue growth and adhesion., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Joint contracture, resulting from a prolonged joint immobilization, is a common complication in orthopedics. Currently, utilizing an internal fixation to restrict knee joint mobility is a widely accepted model to generate experimental contracture. However, implanting application will inevitably cause surgical trauma to the animals. Aiming to develop a less invasive approach, we combined a muscle-gap separation modus with a previously reported mini-incision skill during the surgical procedure: Two mini skin incisions were made on the lateral thigh and leg, followed by performing muscle-gap separation to expose the bone surface. The rat knee joint was gradually immobilized by a preconstructed internal fixation at approximately 135° knee flexion without interfering essential nerves or blood vessels. As expected, this simple technique permits rapid postoperative rehabilitation in animals. The correct position of the internal fixation was confirmed by an x-ray or micro-CT scanning analysis. The range of motion was significantly restricted in the immobilized knee joint than that observed in the contralateral knee joint demonstrating the effectiveness of this model. Besides, histological analysis revealed the development of fibrous deposition and adhesion in the posterior-superior knee joint capsule over time. Thus, this mini-invasive model may be suitable for mimicking the development of immobilized knee joint contracture.

Background: Joint contracture is a fibrous disease characterized as joint capsule fibrosis that results in joint dysfunction and disability. The purpose of this study was to analyze the biological activities of chaperonin containing T-complex polypeptide (CCT) subunits and to determine the role of CCT chaperone in joint contracture in a rat model., Methods: In this study, the rat model of joint contracture was established by immobilizing the rat knee for 8 weeks. Then, fibroblasts were isolated from the posterior joint capsule and were cultured for functional analysis such as qRT-PCR, Western blot, transwell assay, and collagen assay. The effect of CCT subunit was determined by employing a lentivirus containing target gene and transfecting it into fibroblasts., Results: Results of qRT-PCR and Western blot showed that among all CCT subunits, CCT6b significantly decreased in the fibroblasts from contractive joints compared to cells from normal joints (p < 0.05). Overexpression of CCT6b by transfection of lentivirus containing CCT6b gene to active fibroblasts significantly inhibited fibrous marker (α-SMA, COL-1) expressions, fibroblast migration, and collagen synthesis (all p < 0.05). Moreover, fibrosis-related chaperone CCT7 expression was decreased with CCT6b overexpression (p < 0.05)., Conclusion: The biological activities of CCT subunits in fibroblasts from the joint contracture rat model were analyzed in this study. CCT6b significantly decreased in the active fibroblasts, and overexpression of CCT6b significantly inhibited fibroblast functions. These findings indicate that CCT6b appears to be a potential molecular biomarker and therapeutic target for the novel therapies of joint contracture.

Background: Adhesive capsulitis (AC) is a disabling and poorly understood pathological condition of the shoulder joint. The current study aims to increase our understanding of the pathogenesis, diagnosis and clinical outcomes of people with AC by investigating: 1) transcriptome-wide alterations in gene expression of the glenohumeral joint capsule in people with AC compared to people with non-inflammatory shoulder instability (controls); 2) serum and urine biomarkers to better understand diagnosis and staging of AC; and 3) clinical outcomes in people with AC compared to controls 12-months following arthroscopic capsular release or labral repair respectively., Methods: The study is a prospective multi-centre longitudinal study investigating people undergoing arthroscopic capsulotomy for AC compared to people undergoing arthroscopic stabilization for shoulder instability. Tissue samples collected from the anterior glenohumeral joint capsule during surgery will undergo RNA-seq to determine differences in gene expression between the study groups. Gene Set Enrichment Analysis will be used to further understand the pathogenesis of AC as well as guide serum and urine biomarker analysis. Clinical outcomes regarding pain, function and quality of life will be assessed using the Oxford Shoulder Score, Oxford Shoulder Instability Score, Quick DASH, American Shoulder and Elbow Society Score, EQ-5D-5 L and active shoulder range of movement. Clinical outcomes will be collected pre-operatively and 12-months post-operatively and study groups will be compared for statistically significant differences using linear regression, adjusting for baseline demographic variables., Discussion: This study will provide much needed information regarding the pathogenesis, diagnosis and staging of AC. It will evaluate clinical outcomes for people undergoing arthroscopic release of AC by comparing this group to people undergoing arthroscopic surgery for shoulder instability., Trial Registration: ACTRN12618000431224 , retrospectively registered 26 March 2018.

Background and Objectives: Peripheral nerve block is an important component of the multimodal analgesia for total knee arthroplasty. Novel interventional techniques of ultrasound-guided nerve block supplying the posterior knee joint capsule require knowledge of the innervation of the posterior capsule. The objectives of this cadaveric study were to determine the course, frequency, and distribution of the articular branches innervating the posterior knee joint capsule and their relationships to anatomical landmarks., Methods: Fifteen lightly embalmed specimens were meticulously dissected. The origin of articular branches was identified, their frequency recorded, and the course documented in relation to anatomical landmarks. The capsular distribution of articular branches was documented and a frequency map generated., Results: In all specimens, articular branches from the posterior division of the obturator and tibial nerves were found to supply the posterior capsule. Additionally, articular branches from common fibular nerve and sciatic nerve were found in eight (53%) and three (20%) specimens, respectively. The capsular distribution of tibial nerve spanned the entire posterior capsule. The posterior division of obturator nerve supplied the superomedial aspect of the posterior capsule overlapping with the tibial nerve. The superolateral aspect of the posterior capsule was innervated by the tibial nerve and, when present, the common fibular/sciatic nerves., Conclusions: Frequency map of the course and distribution of the articular branches and their relationship to anatomical landmarks form an anatomical basis for peripheral nerve block approaches that provide analgesia to the posterior knee joint capsule., Competing Interests: Competing interests: PWHP received equipment support from Sonosite Fujifilm Canada. VC has received honorarium from Aspen Pharma, BBraun, Smiths Medical, and SonoSite., (© American Society of Regional Anesthesia & Pain Medicine 2019. No commercial re-use. See rights and permissions. Published by BMJ.)