Search

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.)

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.

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.

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).)

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.)

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.

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.)

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.

Introduction: Knee injuries are common in sports, and postinjury immobilization is often required to protect healing tissues and alleviate pain, but both the injury and the immobilization can lead to a knee contracture. Knee flexion contractures limit performance. Previous research has identified posterior knee capsule fibrosis as a contributor to immobility-induced knee flexion contractures. This study aims to measure posterior knee capsule length at various durations of remobilization after knee immobilization and to correlate with the recovery of knee range of motion., Methods: Two hundred fifty-nine male Sprague-Dawley rats had one knee extra-articularly immobilized in flexion with a Delrin® plate at a 45° angle for one of six durations: 1, 2, 4, 8, 16, or 32 wk, followed by spontaneous remobilization after plate removal, which lasted zero, one, two, and four times the duration of immobilization. The contralateral knees served as controls. The posterior knee capsule length was measured by histomorphometry. These measures were correlated with previously published range of motion data from the same cohort of specimens., Results: Knees immobilized for 1 and 2 wk partially recovered posterior capsule length (P > 0.05). Knees immobilized beyond 2 wk failed to recover posterior capsule length, irrespective of the duration of remobilization (P < 0.05). The residual posterior capsule shortening correlated with the lack of knee extension (P < 0.003)., Conclusions: For knee injuries requiring more than 2 wk of immobilization, unassisted remobilization will not restore posterior knee capsule shortening and the reduction in knee extension. These results support the role of the posterior capsule in knee joint contracture and the need to minimize the duration of immobility and to assist the recovery of the range of knee extension after a sport injury.

Background: The elbow is highly susceptible to contracture, which affects up to 50% of patients who experience elbow trauma. Previously, we developed a rat model to study elbow contracture that exhibited features similar to the human condition, including persistently decreased ROM and increased capsule thickness/adhesions. However, elbow ROM was not quantitatively evaluated over time throughout contracture development and subsequent mobilization of the joint., Questions/purposes: The purposes of this study were (1) to quantify the time-dependent mechanics of contracture, including comparison of contracture after immobilization and free mobilization; and (2) to determine what changes occur in capsule and joint surface morphology that may support the altered joint mechanics., Methods: A total of 96 male Long-Evans rats were randomized into control and injury (unilateral soft tissue injury/immobilization) groups. Flexion-extension and pronation-supination joint mechanics (n = 8/group) were evaluated after 3, 7, 21, or 42 days of immobilization (IM) or after 42 days of IM with either 21 or 42 days of free mobilization (63 or 84 FM, respectively). After measuring joint mechanics, a subset of these limbs (n = 3/group) was prepared for histologic analysis and blinded sections were scored to evaluate capsule and joint surface morphology. Joint mechanics and capsule histology at 42 IM and 84 FM were reported previously but are included to demonstrate the full timeline of elbow contracture., Results: In flexion-extension, injured limb ROM was decreased compared with control (103° ± 11°) by 21 IM (70° ± 13°) (p = 0.001). Despite an increase in injured limb ROM from 42 IM (55° ± 14°) to 63 FM (83° ± 10°) (p < 0.001), injured limb ROM was still decreased compared with control (103° ± 11°) (p = 0.002). Interestingly, ROM recovery plateaued because there was no difference between injured limbs at 63 (83° ± 10°) and 84 FM (73° ± 19°) (p > 0.999). In pronation-supination, increased injured limb ROM occurred until 7 IM (202° ± 32°) compared with control (155° ± 22°) (p = 0.001), representative of joint instability. However, injured limb ROM decreased from 21 (182° ± 25°) to 42 IM (123° ± 47°) (p = 0.001), but was not different compared with control (155° ± 22°) (p = 0.108). Histologic evaluation showed morphologic changes in the anterior capsule (increased adhesions, myofibroblasts, thickness) and nonopposing joint surfaces (surface irregularities with tissue overgrowth, reduced matrix), but these changes did not increase with time., Conclusions: Overall, flexion-extension and pronation-supination exhibited distinct time-dependent patterns during contracture development and joint mobilization. Histologic evaluation showed tissue changes, but did not fully explain the patterns in contracture mechanics. Future work will use this rat model to evaluate the periarticular soft tissues of the elbow to isolate tissue-specific contributions to contracture to ultimately develop strategies for tissue-targeted treatments., Clinical Relevance: A rat model of posttraumatic elbow contracture quantitatively described contracture development/progression and reiterates the need for rehabilitation strategies that consider both flexion-extension and pronation-supination elbow motion.

Joint contracture is a common complication for people with joint immobility that involves fibrosis structural alteration in the joint capsule. Considering that endoplasmic reticulum (ER) stress plays a prominent role in the promotion of tissue fibrosis, we investigated whether the unfolded protein response (UPR) contributes to the fibrotic development in immobilization-induced knee joint contractures. Using a non-traumatic rat knee joint contracture model, twelve female Sprague-Dawley rats received knee joint immobilization for a period of 8 weeks. We found that fibrosis protein markers (type I collagen, α-SMA) and UPR (GRP78, ATF6α, XBP1s) markers were parallelly upregulated in rat primary cultured synovial myofibroblasts. In the same cell types, pre-treatment with an ER stress inhibitor, 4-phenylbutyric acid (4-PBA), not only abrogated cytokine TGFβ1 stimulation but also reduced the protein level of UPR. Additionally, high reactive oxygen species (ROS) generation was detected in synovial myofibroblasts through flow cytometry, as expected. Notably, TGFβ1-induced UPR was significantly reduced through the inhibition of ROS with antioxidants. These data suggest that ER stress act as a pro-fibrotic stimulus through the overexpression of ROS in synovial fibroblasts. Interestingly, immunohistochemical results showed an increase in the UPR protein levels both in human acquired joint contractures capsule tissue and in animal knee joint contracture tissue. Together, our findings suggest that ER stress contributes to synovial myofibroblastic differentiation in joint capsule fibrosis and may also serve as a potential therapeutic target in joint contractures., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Joint mobility decreases in the elderly and in diabetics, this process is thought to be caused by accumulation of advanced-glycation end products (AGEs). Here, we aimed to elucidate the role of AGEs in joint contracture formation in rat knees. Rats were injected with ribose or saline into the knees twice weekly for 8 weeks. Pentosidine (AGE) levels were measured in the knee-joint tissues. After serial injections, rats were subjected to unilateral knee-joint immobilization in a flexion position for various periods. At day 21, the passive knee ranges of motions (ROMs) were measured. Knee joint histopathology were assessed, and the expression of fibrotic genes in the posterior joint capsules was examined using real-time PCR. Ribose injection induced a 7.0-fold increase in pentosidine levels relative to saline injection. Joint immobilization resulted in equal myogenic ROM restriction in both groups. Arthrogenic ROM restriction was greater with ribose injection in the immobilized joints (p < 0.05), but was not affected in nonimmobilized joints. Type-I (COL1A1) and type-III (COL3A1) collagen gene expression increased significantly in immobilized joints relative to nonimmobilized joints in the ribose group, but was not affected in the saline group. Ribose injection increased COL1A1 expression slightly and COL3A1 expression significantly in immobilized joints. Histologically, inflammatory changes appeared at day 3 of immobilization and peaked at day 7. These responses trended to be more severe and prolonged in the ribose group than in the saline group. Our data provide evidence for a causal relationship between AGEs and joint contracture formation following immobilization. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:854-863, 2018., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

This study investigated the effects of treadmill walking during remobilization on range of motion (ROM) and histopathology in rat knee joints, which were immobilized for 3 wk in a flexed position. After fixator removal, rats were divided into a no-intervention (RM) group and a group forced to walk on a treadmill daily at 12 m/min for 60 min (WALK group). Passive knee extension ROMs were measured before (m-ROM) and after (a-ROM) knee flexor myotomy on the first and last day of a 7-day remobilization period, with m-ROM mainly reflecting myogenic factors and a-ROM reflecting arthrogenic factors. Knee joints were histologically analyzed and gene expression of inflammatory or fibrosis-related mediators in the posterior joint capsule were examined. m-ROM and a-ROM restrictions were established after immobilization. m-ROM significantly increased following the remobilization period both in RM and WALK groups compared with that of immobilized (IM) group. Conversely, a-ROM decreased following the remobilization period in both RM and WALK groups compared with that of IM group. Importantly, a-ROM was smaller in the WALK group than the RM group. Remobilization without intervention induced inflammatory and fibrotic reactions in the posterior joint capsule after 1 and 7 days. Treadmill walking promoted these reactions and also increased the expression of fibrosis-related TGF-β1 and collagen type I and III genes. While free movement after immobilization improved myogenic contracture, arthrogenic contracture worsened. Treadmill walking further aggravated arthrogenic contracture through amplified inflammatory and fibrotic reactions. Thus active exercise immediately after immobilization may not improve immobilization-induced joint contracture. NEW & NOTEWORTHY In clinical practice, it is widely accepted that facilitation of joint movements is effective in improving immobilization-induced joint contracture. However, whether active exercises improve arthrogenic contracture is not known. In this study, we revealed that treadmill walking further promoted remobilization-induced progression of arthrogenic contracture. To our knowledge, this is the first study demonstrating no favorable effect of active exercise on immobilization-induced arthrogenic contracture.

Objectives: A knee joint contracture, a loss in passive range of motion (ROM), can be caused by prolonged immobility. In a rat knee immobilization flexion contracture model, the posterior capsule was shown to contribute to an irreversible limitation in ROM, and collagen pathways were identified as differentially expressed over the development of a contracture. Collagenases purified from Clostridium histolyticum are currently prescribed to treat Dupuytren's and Peyronie's contractures due to their ability to degrade collagen. The potential application of collagenases to target collagen in the posterior capsule was tested in this model., Materials and Methods: Rats had one hind leg immobilized, developing a knee flexion contracture. After 4 weeks, the immobilization device was removed, and the rats received one 50 µL intra-articular injection of 0.6 mg/mL purified collagenase. Control rats were injected with only the buffer. After 2 weeks of spontaneous remobilization following the injections, ROM was measured with a rat knee arthrometer, and histological sections were immunostained with antibodies against rat collagen types I and III., Results/conclusion: Compared with buffer-injected control knees, collagenase-treated knees showed increased ROM in extension by 8.0°±3.8° ( p -value <0.05). Immunohistochemical analysis revealed an increase in collagen type III staining ( p <0.01) in the posterior capsule of collagenase-treated knees indicating an effect on the extracellular matrix due to the collagenase. Collagen I staining was unchanged ( p >0.05). The current study provides experimental evidence for the pharmacological treatment of knee flexion contractures with intra-articular collagenase injection, improving the knee ROM., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The purpose of this study was to examine the time-dependent changes in the development of joint capsule fibrosis and in the number of myofibroblasts in the joint capsule after immobilization, using a rat knee contracture model. Both knee joints were fixed in full flexion for 1, 2, and 4 weeks (immobilization group). Untreated rats were bred for each immobilization period (control group). Histological analysis was performed to evaluate changes in the amount and density of collagen in the joint capsule. The changes in type I and III collagen mRNA were examined by in situ hybridization. The number of myofibroblasts in the joint capsule was assessed by immunohistochemical methods. In the immobilization group, the amount of collagen increased within 1 week and the density of collagen increased within 2 weeks, as compared with that in the control group. Type I collagen mRNA-positive cell numbers in the immobilization group increased at all time points. However, type III collagen mRNA-positive cell numbers did not increase. Myofibroblasts in the immobilization group significantly increased compared with those in the control group at all time points, and they increased significantly with the period of immobilization. These results suggest that joint capsule fibrosis with overexpression of type I collagen occurs and progresses within 1 week after immobilization, and an increase in myofibroblasts is related to the mechanism of joint capsule fibrosis. The findings suggest the need for a treatment targeting accumulation of type I collagen associated with an increase in myofibroblasts. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1998-2006, 2017., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

This study aimed to elucidate how rats recover from immobilization-induced knee joint contracture. Rats' right knees were immobilized by an external fixator at a flexion of 140° for 3 weeks. After removal of the fixator, the joints were allowed to move freely (remobilization) for 0, 1, 3, 7, or 14 days (n = 5 each). To distinguish myogenic and arthrogenic contractures, the passive extension range of motion was measured before and after myotomy of the knee flexors. Knee joints were histologically analyzed and the expression of genes encoding inflammatory or fibrosis-related mediators, interleukin-1β (1L-1β), fibrosis-related transforming growth factor-β1 (TGF-β1), and collagen type I (COL1A1) and III (COL3A1), were examined in the knee joint posterior capsules using real-time PCR. Both myogenic and arthrogenic contractures were established within 3 weeks of immobilization. During remobilization, the myogenic contracture decreased over time. In contrast, the arthrogenic contracture developed further during the remobilization period. On day 1 of remobilization, inflammatory changes characterized by edema, inflammatory cell infiltration, and upregulation of IL-1β gene started in the knee joint posterior capsule. In addition, collagen deposition accompanied by fibroblast proliferation, with upregulation of TGF-β1, COL1A1, and COL3A1 genes, appeared in the joint capsule between days 7 and 14. These results suggest the progression of arthrogenic contracture following remobilization, which is characterized by fibrosis development, is possibly triggered by inflammation in the joint capsule. It is therefore necessary to focus on developing new treatment strategies for immobilization-induced joint contracture. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1414-1423, 2017., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Post-traumatic joint stiffness (PTJS) of the elbow is a debilitating condition that poses unique treatment challenges. While previous research has implicated capsular tissue in PTJS, much regarding the development and progression of this condition remains unknown. The objective of this study was to develop an animal model of post-traumatic elbow contracture and evaluate its potential for studying the etiology of PTJS. The Long-Evans rat was identified as the most appropriate species/breed for development due to anatomical and functional similarities to the human elbow joint. Two surgical protocols of varying severity were utilized to replicate soft tissue damage seen in elbow subluxation/dislocation injuries, including anterior capsulotomy and lateral collateral ligament transection, followed by 6 weeks of unilateral joint immobilization. Following sacrifice, flexion-extension mechanical joint testing demonstrated decreased range-of-motion and increased stiffness for injured-immobilized limbs compared to control and sham animals, where functional impact correlated with severity of injury. Histological evaluation showed increased cellularity, adhesion, and thickness of capsule tissue in injured limbs, consistent with clinical evidence. To our knowledge, this is the first animal model capable of examining challenges unique to the anatomically and biomechanically complex elbow joint. Future studies will use this animal model to investigate mechanisms responsible for PTJS., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Joint contracture is a fibroproliferative disorder that restricts joint mobility, resulting in tissue degeneration and deformity. However, the etiology of joint contracture is still unknown. Chaperonin containing T-complex polypeptide subunit eta (CCT-eta) is reported to increase in fibrotic diseases. The purpose of this study was to investigate whether CCT-eta is implicated in joint contracture and to determine the role of CCT-eta in the progression of joint contracture by analyzing a rat model. We immobilized the left knee joint of rat by internal fixation for 8 weeks. The non-immobilized right leg served as a control. The range of motion (ROM) of the knee was investigated. Fibroblasts were obtained from the posterior joint capsule of the joints. The outcome was followed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, fibroblast migration assay, and collagen assay. The effect of CCT-eta on the functions of fibroblasts was observed by utilizing a short inhibitory RNA (siRNA) targeting CCT-eta. The ROM of the immobilized joints was significantly limited compared to the contralateral joints (p < 0.05). Fibroblasts derived from the contractive joints showed higher mRNA and protein expressions of CCT-eta in parallel with alpha-smooth muscle actin (α-SMA) compared to the cells from the contralateral knees (p < 0.05). siRNA-mediated downregulation of CCT-eta inhibited the expressions of both CCT-eta and α-SMA. Moreover, the reduction of CCT-eta also significantly decreased fibroblast functions such as cell mobility and collagen synthesis (all p < 0.05). Our findings indicate that CCT-eta appears to be a potential marker of joint contracture disease.

Objective: To (1) identify demographic and clinical factors associated with knee flexion contracture (KFlC) in the setting of osteoarthritis (OA) and (2) histologically compare the posterior knee capsule of patients with OA with and without KFlC., Design: Cross-sectional study., Setting: Primary care, including private and institutional practice., Patients: Thirteen patients with primary OA and KFlC and 8 patients with primary OA without KFlC., Methods: We compared the KFlC and non-KFlC groups to identify demographic and clinical factors associated with KFlC. We examined the histology of the posterior knee capsules of 9 patients with KFlC and 6 without., Main Outcome Measurements: Patient demographic and clinical factors. For histology we measured the proportional composition of collagenous, adipose, and synovial tissues; fibroblast and adipocyte cellularity; and synovial thickness., Results: Patients with contracture had longer duration of OA, reduced flexion of the surgical knee, and reduced extension of the contralateral knee (P = .04, <.01, and <.01 respectively). Histologically, there was a greater proportion of collagenous tissue and a lower proportion of adipose and synovial tissues in the contracture group than in the noncontracture group; however, the differences were not statistically significant. Cellularity was similar between the 2 groups., Conclusions: Longer duration of knee OA, reduced surgical knee flexion, and reduced contralateral, nonsurgical knee extension were associated with KFlC in the OA knee undergoing total arthroplasty. Monitoring bilateral knee range of motion in patients with longer-duration OA could allow earlier intervention, reducing functional loss. Capsular tissue composition analysis may indicate a fibrotic disease process. Further research in which a larger sample size is used will help clarify these novel findings., (Copyright © 2015 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

Purpose: To elucidate preventive effects of high molecular weight hyaluronan (HMWHA) on the joint capsule of immobilized knees in rats., Materials and Methods: Unilateral knee joints of rats were immobilized with an internal fixator. Either 50 μl of HMWHA (Im-HA group) or 50 μl of saline (control group) was administered intra-articularly once a week after surgery. Sagittal sections were prepared from the medial midcondylar region of the knee joints and assessed by histological, histomorphometric, and immunohistochemical methods. Gene expressions related to inflammation, fibrotic conditions, and hypoxia were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Tissue elasticity of the capsule from both groups was examined using a scanning acoustic microscope (SAM)., Results: CD68 positive cells decreased in adhesion areas of the synovial membrane after 1 week in both groups. The length of the superficial layer in the synovial membrane of the Im-HA group was significantly longer than those in the control group over a period of 4 to 8 weeks with significantly small numbers of CD68 positive cells. The gene expressions of IL-6, IL-1β, TGF-β, CTGF, COL1a1, COL3a1, SPARC, and HIF1-α were significantly lower in the Im-HA group compared to those in the control group. The sound speed of the anterior and posterior synovial membrane increased significantly (a reduction in elasticity) in the control group compared to those in the Im-HA group during weeks 1 to 4., Conclusions: This study demonstrated that HMWHA injections suppressed inflammatory, fibrotic, and hypoxic conditions observed in the immobilized joint capsule.

Purpose: To elucidate the effects of intra-articular haemorrhage on the joint capsule of immobilized knees in rats., Methods: The unilateral knee joints were immobilized using a plastic plate and screws. Sham operated rats had only screws inserted. A single injection of fresh autologous blood was given postoperatively into the knee joints of the immobilized blood injection (Im-B) and the Sham blood injection (Sm-B) groups. Normal saline was administered for the immobilized-saline injection (Im-S) group. Sagittal sections were prepared from the medial midcondylar region of the knee and assessed with histological, histomorphometric, and immunohistochemical methods. The range of motion (ROM) was measured, and the mechanical property of the capsule was assessed by scanning acoustic microscope., Results: Absorption of the injected blood was delayed and made severe adhesions in the Im-B group. The length of the synovial membrane in the Im-B group was significantly shorter than that of the other groups. The ROM was significantly restricted in the Im-B group compared with the other groups. The elasticity of the posterior capsule in the Im-B group was significantly lower than that in the Sm-B group. Iron deposition was observed in the Im-B and Sm-B groups. Strong immunoreactivities of CD68, TGF-β1, and α-SMA were observed in the adhesion area of the Im-B group. Joint immobilization with blood injection caused severe capsular adhesion and limited range of motion. Immunostaining related to fibrosis increased with joint haemorrhage., Conclusion: Intra-articular haemorrhage with joint immobilization might be an accelerated risk factor for joint contracture. It is likely that leaving a haematoma inside an immobilized joint should be avoided.

Objective: Knee flexion contractures (KFC) are limitations in the ability to fully extend the knee joint. In people with knee osteoarthritis (OA), KFC are common, impair function, and worsen outcomes after arthroplasty. In KFC, the posterior knee capsule is believed to play a key role, but the pathophysiology remains poorly understood. We sought to identify gene expression differences in the posterior knee capsule of patients with OA with and without KFC., Methods: Capsule tissue was obtained from the knees of 12 subjects diagnosed with advanced-stage OA at the time of knee arthroplasty surgery. The presence or absence of KFC allocated patients into 2 groups using a case-control design. Genomewide capsular gene expression was compared between the 2 patient groups. Confirmation of differential expression of the corresponding proteins was performed by immunohistochemistry on tissue sections., Results: There were no significant demographic differences between the patients with OA with KFC and without KFC save for reduced extension in their surgical knee (p<0.01). KFC patients showed a 6.4-fold decrease in CSN1S1 (p=0.017) gene expression and a 3.7-, 2.0-, and 2.6-fold increase in CHAD, Sox9, and Cyr61 gene expression, respectively (p=0.001, 0.004, 0.001, respectively). There were corresponding increases in protein levels for chondroadherin, sex determining region Y-box 9, and casein alphaS1 (all p<0.05). Functional analysis of the differentially expressed genes indicated a strong association with pathways related to the extracellular matrix and to tissue fibrosis., Conclusion: Posterior capsules in endstage OA knees with KFC exhibited differential expression of 4 genes all previously documented to be associated with tissue fibrosis.

Previous studies have implicated a myofibroblast-mast cell-neuropeptide axis of fibrosis in pathologic joint capsules from post-traumatic contractures. The hypothesis to be tested is that joint capsule cells (JC) from human elbows with post-traumatic contractures and their interactions with mast cells (MC) and neuropeptides in the microenvironment underlie the pathogenesis of contractures. The hypothesis was tested using an in vitro collagen gel contraction model. The JC were isolated from human elbow capsules and mixed with neutralized PureCol collagen I. The gels were treated in various ways, including addition of MC (HMC-1), the neuropeptide substance P (SP), an NK1 receptor (SP receptor) antagonist RP67580 and the mast cell stabilizer ketotifen fumarate (KF). The collagen gels were released from the wells and gel size (contraction) was measured optically at multiple time points. The JC contracted collagen gels in a dose-dependent manner. This was enhanced in the presence of MC and increased further with SP. Increasing concentrations of the SP receptor antagonist, RP67580 or the mast cell stabilizer, KF decreased the magnitude of contraction. These observations identify putative mechanistic components of a myofibroblast-mast cell-neuropeptide axis of fibrosis in the joint capsules in post-traumatic contractures and potential prophylactic or therapeutic interventions., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Joint contractures are a common complication of many neurologic conditions, and stretching often is advocated to prevent and treat these contractures. However, the magnitude and duration of the stretching done in practice usually are guided by subjective clinical impressions., Questions/purposes: Using an established T8 spinal cord injury rat model of knee contracture, we sought to determine what combination of static or intermittent stretching, varied by magnitude (high or low) and duration (long or short), leads to the best (1) improvement in the limitation in ROM; (2) restoration of the muscular and articular factors leading to contractures; and (3) prevention and treatment of contracture-associated histologic alterations of joint capsule and articular cartilage., Methods: Using a rat animal model, the spinal cord was transected completely at the level of T8. The rats were randomly assigned to seven treatment groups (n = 4 per group), which were composed of static or intermittent stretching in combination with different amounts of applied torque magnitude and duration. We assessed the effect of stretching by measuring the ROM and evaluating the histologic alteration of the capsule and cartilage., Results: Contractures improved in all treated groups except for the low-torque and short-duration static stretching conditions. High-torque stretching was effective against shortening of the synovial membrane and adhesions in the posterosuperior regions. Collagen Type II and VEGF in the cartilage were increased by stretching., Conclusions: High-torque and long-duration static stretching led to greater restoration of ROM than the other torque and duration treatment groups. Stretching was more effective in improving articular components of contractures compared with the muscular components. Stretching in this rat model prevented shortening and adhesion of the joint capsule, and affected biochemical composition, but did not change morphologic features of the cartilage., Clinical Relevance: This animal study tends to support the ideas that static stretching can influence joint ROM and histologic qualities of joint tissues, and that the way stretching is performed influences its efficacy. However, further studies are warranted to determine if our findings are clinically applicable.

The Andrew J. Weiland Medal is presented by the American Society for Surgery of the Hand to a midcareer researcher who is dedicated to advancing patient care in the field of hand surgery. This essay, awarded the Weiland Medal in 2012, focuses on posttraumatic elbow joint contractures. Joint contractures are well known to hand surgeons because they limit function of our patients. There is a thorough understanding of the pathoanatomy underlying joint contractures. However, the mechanisms leading to the pathoanatomy are either unknown or partially understood, depending on the etiology of the particular clinical condition. This review describes our research over the past 14 years on posttraumatic elbow joint contractures. It defines pathologic cellular, matrix, and growth factor changes in the joint capsule, elaborates on the development of an animal model of posttraumatic joint contractures, presents an evaluation of a potential prevention strategy based on our research, and outlines future plans to bring this work to the clinical realm for the benefit of patients., (Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Posttraumatic elbow stiffness remains a common and challenging clinical problem. In the setting of a congruent articular surface, the joint capsule is regarded as the major motion-limiting anatomic structure. The affected joint capsule is characterized by irreversible biomechanical and biochemical fibrogenic changes strikingly similar to those observed in many other fibroproliferative human conditions. Studies in humans and preclinical animal models are providing emergent evidence that neuroinflammatory mechanisms are critical upstream events in the pathogenesis of posttraumatic connective tissue fibrogenesis. Maladaptive recruitment and activation of mast cell infiltrates coupled with the aberrant expression of growth factors such as transforming growth factor-beta, nerve growth factor, and neuropeptides such as substance P are common observations in posttraumatic joint contractures and many other fibroproliferative disorders. Blockade of these factors is providing promising evidence that if treatment is timed correctly, the fibrogenic process can be interrupted or impeded. This review serves to highlight opportunities derived from these recent discoveries across many aberrant fibrogenic disorders as we strive to develop novel, targeted antifibrotic prevention and treatment strategies for posttraumatic elbow stiffness.

Extracellular signal-regulated kinase (ERK)-2 is presumed to play an important role in the development of post-traumatic joint contractures. Using a rat injury model, we investigated whether treatment with ERK2 small interfering RNA (siRNA) could reduce the extent of joint capsule fibrosis after an induced injury. Rats were separated into three groups (n = 32 each): non-operated control group, operated contracture group and contracture-treatment group. Stable post-traumatic joint contracture was created through surgical intra-articular joint injury followed by eight weeks of immobilization. In the contracture-treatment group, the rats were treated with lentivirus (LV)-mediated ERK2 siRNA at days 3 and 7 post-surgery. The posterior joint capsule was assessed by western blotting, immunohistochemistry and biochemical analysis for changes in ERK2, phosphorylated (p)-ERK2, myofibroblast, total collagen and relative collagen Type III expression level. Biomechanical testing was used to assess the development of flexion contractures. Statistical analysis was performed using an analysis of variance. In the operated contracture group, rats that developed flexion contractures also showed elevated phosphorylated p-ERK2 expression. In the contracture-treatment group, ERK2 siRNA significantly reduced p-ERK2 expression levels, as well as the severity of flexion contracture development (p < 0.01). Myofibroblast numbers and measurements of total collagen content were also significantly reduced following ERK2 siRNA (p < 0.01). Relative collagen type III expression as a proportion of total of Types I and III collagen, however, was significantly increased in response to ERK2 siRNA (p < 0.01). Our findings demonstrate a role for ERK2 in the induction of joint capsule fibrosis after injury. Furthermore, we show that development of flexion contractures and the resultant increase of joint capsule fibrosis can be reduced by LV-mediated ERK2 siRNA treatment.

We describe 4 patients with an extension contracture of the little metacarpophalangeal joint without definite cause. We encountered this entity only in adolescent girls. When treated conservatively, we observed no improvements in motion. The main pathology of this entity was a hypertrophied dorsal capsule. The 2 patients treated by surgical release of the fifth dorsal capsule and collateral ligaments achieved considerable flexion 2 years later., (Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Studies have demonstrated increased myofibroblasts in contractures. However, the timeline is largely unknown. The aim of this study was to determine the number of myofibroblasts in contracting joint capsules at 3-time points over a 24-week period. Eighteen rabbits subjected to a surgical procedure designed to elicit a knee joint contracture were divided into three groups of six. Rabbits were sacrificed at each respective time point and myofibroblasts in the joint capsules were quantified using immunohistochemistry. The percent of myofibroblasts was significantly elevated in the operated limbs compared to the control limbs at 2 weeks (20% vs. 7%, respectively; p = 0.014). There was no difference in the percent of myofibroblasts between the operated and control limbs at 8 or 24 weeks (p = 0.96 and 0.07, respectively). The percent of myofibroblasts dropped from 20% at 2 weeks to 3.0% at 8 weeks (p < 0.001). The decrease from 8 to 24 weeks was not significant (p = 0.19). A large proportion of myofibroblasts are present in contracted joints at 2 weeks. By week 8, the proportion of myofibroblasts seem to return to normal. Interventions aimed at affecting the myofibroblast cell in order to prevent fibrosis should be instituted early., (Copyright © 2011 Orthopaedic Research Society.)

Joint immobilization, which is used in orthopaedic treatments and observed in bedridden people, usually causes restricted joint motion. Decreased joint motion diminishes activities of daily living and increases burden of nursing-care. The purpose of this study was to clarify the reversibility of immobilization-induced capsular changes and restricted joint motion in rat knee joints. The unilateral knee joints of adult male rats were immobilized with an internal fixator for 1, 2, 4, 8, and 16 weeks as a model of immobilization after surgery or disuse of the joint. After the fixation devices were removed, the rats were allowed to move freely for 16 weeks. Sham-operated rats were used as controls. Sagittal sections at medial midcondylar regions were made and assessed with histological, histomorphometric, and immunohistochemical methods. Joint motion was measured using a custom-made device under x-ray control after removal of the periarticular muscles. In the 1/16-week and 2/16-week immobilization-remobilization (Im-Rm) groups, cord-like structures connecting the superior and inferior portions of the posterior capsule (partial adhesion) were observed without restricted joint motion. In the 4/16-, 8/16-, and 16/16-week Im-Rm groups, global adhesion of the posterior capsule and restricted joint motion were observed. The restricted joint motion was not completely restored after incision of the posterior capsule. These data indicate that immobilization alone causes irreversible capsular changes and arthrogenic restricted joint motion. Besides the joint capsule, other arthrogenic factors such as ligaments might influence the restricted joint motion. Prolonged immobilization over 4 weeks should be avoided to prevent irreversible joint contracture.

Objectives: Using a rabbit model of post-traumatic joint contractures, we investigated whether treatment with a mast cell stabilizer after joint injury would lessen the molecular manifestations of joint capsule fibrosis., Methods: Surgical joint injury was used to create stable post-traumatic contractures of the knee in skeletally mature New Zealand white rabbits. Four groups of animals were studied: a non-operated control group (n = 8), an operated contracture group (n = 13) and two operated groups treated with the mast cell stabilizer, ketotifen, at doses of 0.5 mg/kg (n = 9) and 1.0 mg/kg (n = 9) twice daily. Joint capsule fibrosis was assessed by quantifying the mRNA and protein levels of α-SMA, tryptase, TGF-β1, collagen I and collagen III. Significance was tested using an ANOVA analysis of variance., Results: The protein and mRNA levels of α-SMA, TGF-β1, tryptase and collagen I and III were significantly elevated in the operated contracture group compared to control (p < 0.01). In both ketotifen-treated groups, protein and mRNA levels of α-SMA, TGF-β1 and collagen I were significantly reduced compared to the operated contracture group (p < 0.01)., Conclusions: These data suggest an inflammatory pathway mediated by mast cell activation is involved in joint capsule fibrosis after traumatic injury.

Introduction: Previous studies have shown that the number of myoblastically differentiated fibroblasts known as myofibroblasts (MFs) is significantly increased in stiff joint capsules, indicating their crucial role in the pathogenesis of post-traumatic joint stiffness. Although the mode of MFs' function has been well defined for different diseases associated with tissue fibrosis, the underlying mechanisms of their regulation in the pathogenesis of post-traumatic joint capsule contracture are largely unknown., Methods: In this study, we examined the impact of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) on cellular functions of human joint capsule MFs. MFs were challenged with different concentrations of TNF-alpha with or without both its specifically inactivating antibody infliximab (IFX) and cyclooxygenase-2 (COX2) inhibitor diclofenac. Cell proliferation, gene expression of both alpha-smooth muscle actin (alpha-SMA) and collagen type I, the synthesis of prostaglandin derivates E2, F1A, and F2A, as well as the ability to contract the extracellular matrix were assayed in monolayers and in a three-dimensional collagen gel contraction model. The alpha-SMA and COX2 protein expressions were evaluated by immunofluorescence staining and Western blot analysis., Results: The results indicate that TNF-alpha promotes cell viability and proliferation of MFs, but significantly inhibits the contraction of the extracellular matrix in a dose-dependent manner. This effect was associated with downregulation of alpha-SMA and collagen type I by TNF-alpha application. Furthermore, we found a significant time-dependent upregulation of prostaglandin E2 synthesis upon TNF-alpha treatment. The effect of TNF-alpha on COX2-positive MFs could be specifically prevented by IFX and partially reduced by the COX2 inhibitor diclofenac., Conclusions: Our results provide evidence that TNF-alpha specifically modulates the function of MFs through regulation of prostaglandin E2 synthesis and therefore may play a crucial role in the pathogenesis of joint capsule contractures.

The purpose of this article was to determine mast cell and neuropeptide nerve fiber numbers in joint capsules in posttraumatic contractures, as elevated numbers have been implicated in other fibrotic and contracture conditions. Twelve skeletally mature rabbits had intraarticular cortical windows removed from the medial and lateral femoral condyles and the knee joint immobilized. The contralateral unoperated limb served as a control. Equal numbers of rabbits were sacrificed 4 weeks after surgery or 40 weeks after the first surgery that included 32 weeks of remobilization. Six patients with chronic posttraumatic elbow joint contractures and six age-matched organ donor controls free of elbow contractures were also studied. Joint capsule myofibroblast, mast cell, and neuropeptide containing nerve fiber numbers were assessed with immunohistochemistry. The numbers of myofibroblasts, mast cells, and neuropeptide containing nerve fibers expressed as a percentage of total cells were significantly greater in the contracture capsules when compared to the control capsules at all time points (p < 0.0001). The range of percentages for the three components in the contracture capsules versus the controls were 41-48% versus 9-10%, 44-50% versus 11-13%, and 45-50% versus 10-12% for the acute and chronic stages of the rabbit model and the chronic stages in the human elbows, respectively. These data support the hypothesis that a myofibroblast-mast cell-neuropeptide fibrosis axis may underlie some of the pathologic changes in the joint capsule in posttraumatic contractures. Approaches designed to manipulate this axis, such as preventing degranulation of mast cells, warrant further investigation., ((c) 2008 Orthopaedic Research Society.)

Background and Purpose: A recently developed animal model of posttraumatic contractures reflects the chronic stages of the human condition. To understand the initiation of the process, we evaluated the cellular, matrix, and growth factor changes in the joint capsule in the early stages of the animal model, which would not be possible in humans., Methods: 18 skeletally mature rabbits had intraarticular cortical windows removed from the medial and lateral femoral condyles, and the knee joint was immobilized. The contralateral unoperated limb served as a control. Equal numbers of rabbits were killed 2,4, and 6 weeks after surgery. Myofibroblast, mRNA, and protein determinations were done with immunohistochemistry, RT-PCR, and western blot, respectively., Results: Myofibroblast numbers were statistically significantly elevated in the joint capsules of the experimental knees as compared to control knees. The mRNA and protein levels for collagen types I and III, matrix metalloproteinases 1 and 13, and transforming growth factor beta1 were statistically significantly greater, and for tissue inhibitor of matrix metalloproteinases 1 significantly less, in the experimental capsules than in the control capsules., Interpretation: The experimental joint capsule changes in the acute stages of posttraumatic contractures are similar to those in the chronic stages of the process in this model. Thus, it appears that the mechanisms that attenuate the acute stages of the response to injury are circumvented, contributing to a prolonged modulation of myofibroblast numbers, matrix molecules and growth factors, and leading to joint contractures. Thus, in clinical practice, new approaches to prevention of posttraumatic contractures should be implemented as soon as possible.

Because the use of arthroscopy has increased recently for the treatment of elbow lesions, reports of complications have become more common. Nerve injury after arthroscopic anterior capsular release is an extremely rare complication, with 4 reported cases worldwide. We usually use a sharp-tipped electrocautery device with a 0.5-mm diameter during arthroscopic capsular release. In this case, because the former was not prepared, we used a ball-tipped electrocautery device with a 3-mm diameter. Herein, we experienced a case of radial nerve palsy after arthroscopic anterior capsular release using a ball-tipped electrocautery device on a degenerative elbow contracture. We supposed that the electrocautery device caused transiently thermal injury of the radial nerve despite proper portal entry site, intra-articular distension, and gentle arthroscopic manipulation. Elbow arthroscopy remains a technically difficult procedure with the potential for neurologic complications. To perform surgery safely, knowledge of the regional neuroanatomy and a thorough understanding of proper instrument usage are required.

Stiffness in primary (idiopathic) frozen shoulders has been attributed to a global fibroplasia of the capsule despite the fact surgical release of the capsule at the rotator interval and of the coracohumeral ligament restores motion in almost all patients. Occurrence of vimentin, a cytocontractile protein known to be present in Dupuytren's contracture and in club-feet, has been reported in resection specimens of anterior capsular structures. We hypothesized vimentin would occur only in the anterior structures but fibroplasia would occur throughout the capsule. Tissues removed from four patients were stained with antibodies against vimentin, allowing us to confirm its presence in only in anterior capsular structures, supporting our first hypothesis contracture is due to a selective involvement of the anterior capsule. Staining the sections against types I and III collagen permitted the detection of both collagens in the anterior and the posterior capsular structures and thus confirmed our second hypothesis that fibroplasia involves the entire joint capsule. Therefore it seems, in patients with primary frozen shoulder, fibroplasia and contracture are two distinct processes.

Posterior capsular contracture is a common cause of shoulder pain in which the patient presents with restricted internal rotation and reproduction of pain. Increased anterosuperior translation of the humeral head occurs with forward flexion and can mimic the pain reported with impingement syndrome; however, the patient with impingement syndrome presents with normal range of motion. Initial management of posterior capsular contracture should be nonsurgical, emphasizing range-of-motion stretching with the goal of restoring normal motion. For patients who fail nonsurgical management, arthroscopic posterior capsule release can result in improved motion and pain relief. In the throwing athlete, repetitive forces on the posteroinferior capsule may cause posteroinferior capsular hypertrophy and limited internal rotation. This may be the initial pathologic event in the so-called dead arm syndrome, leading to a superior labrum anteroposterior lesion and, possibly, rotator cuff tear. Management involves regaining internal rotation such that the loss of internal rotation is not greater than the increase in external rotation. In the athlete who fails nonsurgical management, a selective posteroinferior capsulotomy can improve motion, reduce pain, and prevent further shoulder injury.

The joint capsule is a key component in posttraumatic joint contractures. The capsule is described as thickened, but little data exist supporting the observation. Our hypotheses were that mRNA levels of (1) collagen; (2) decorin and biglycan; (3) matrix metalloproteinases; and (4) tissue inhibitors of matrix metalloproteinases were significantly elevated in anterior joint capsules obtained from 11 patients having surgery for posttraumatic contractures when compared with nine elbows, from organ donors, that were free of contractures. Reverse transcription-polymerase chain reaction was used to evaluate mRNA expression normalized to a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase. In the joint capsules of the patients with elbow contractures, relative mRNA levels were increased for: collagen Types I, III, and V (1.5-2.5 times); biglycan (1.5 times); and matrix metalloproteinases-1, -2, -9, -13, and -15 (1.6-3.9 times). In contrast, expression of tissue inhibitors of matrix metalloproteinases-1, -2, and -4 were decreased (1/3-3/4 times) in the capsules of patients with contractures. There was no difference between the groups in relative mRNA expression for decorin, matrix metalloproteinases-8, -14 and -16, and tissue inhibitor of matrix metalloproteinase-3. The results indicate that joint capsule matrix molecule mRNA levels are altered in the chronic stages of posttraumatic elbow contractures in humans, potentially creating an environment with high matrix turnover rates.

The development of joint contracture is a well-recognized complication of elbow injury. Precise causes of the propensity of this joint for ankylosis are understood poorly. Yet, treatment is emerging and therefore the indications and willingness on the part of the surgeon to address this problem is improving. Limited open procedures have emerged during the past several years that are safe and effective by improving arcs of motion of 50-70 degrees in approximately 80-90% of patients. For severe injuries that involve the articular surface, interposition arthroplasty is less documented but has been shown to be effective but constitutes one of the most challenging technical procedures. Joint replacement arthroplasty generally should not be considered as a treatment for posttraumatic stiffness unless the patient is older than 65 years. The experience with this procedure indicates that with linked semiconstrained implants, approximately 80% of patients will achieve a near functional arc of motion. Arthroscopic intervention shows the greatest activity of investigation and clinical expansion. The learning curve is defined by a concern of complications to the neural structures and the fear of this complication has limited the application but the emerging documentation of the safeness of this option also has been associated with improved effectiveness. Therefore, arthroscopic intervention for the stiff elbow, particularly those with soft tissue extrinsic involvement, is emerging as the treatment of choice in many instances. The investigation regarding the medical treatment of altering the tendency of the soft tissue to go through such intense contracture is in its infancy but suggests that this could be a long-term solution at least for many patients.

Elbow contractures, a frequent problem after injury, can be treated by excision of the joint capsule. However, the underlying changes in the joint capsule are poorly understood. Based on skin healing work, we examined the hypotheses that myofibroblast numbers and expression of a myofibroblast marker alpha-smooth muscle actin, are elevated in patients with posttraumatic joint contractures. Anterior capsules were obtained from six patients who had operative release of posttraumatic contractures greater than 5 months after injury and six elbows of organ donors free of contractures. Immunohistochemical studies revealed that myofibroblast numbers and percentage of total cells that were myofibroblasts were significantly elevated in the joint capsules from patients with contractures (326 +/- 61 cells per field, 36% +/- 4% total cells) when compared with similar tissues of the organ donors (69 +/- 41 cells per field, 9% +/- 4% total cells). Western blot analysis showed that protein levels of alpha-smooth muscle actin were significantly elevated in patients with posttraumatic joint contractures. However, analysis with reverse transcription-polymerase chain reaction determined that messenger ribonucleic acid levels for smooth muscle actin normalized to the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase were not significantly different between the two groups. An association between increased numbers of myofibroblasts and posttraumatic joint contractures has been established in the human elbow capsule. Additional work is required to determine whether myofibroblast regulators may be targets for adjuvant therapies of posttraumatic contractures.

Summary: Limitation of internal rotation has been reported in conjunction with impingement syndrome of the shoulder. A group of 9 patients was identified who had discrete, painful loss of internal rotation associated with refractory impingement syndrome. The duration of symptoms averaged 18 months (range, 11 to 33 months), and all patients failed a course of physical therapy specifically addressing loss of internal rotation. Six patients reported traction as the mechanism of injury, and 3 developed motion loss and pain following a posterior capsular shift procedure. All patients underwent arthroscopy, and were observed to have a thickened posterior capsule. An arthroscopic release of the posterior capsule improved motion in all patients, with substantial relief of pain. At an average of 19 months follow-up (range, 11 to 35 months), internal rotation in 90 degrees of abduction improved from 10 degrees preoperatively to 47 degrees postoperatively, and there were no complications related to the procedure. We conclude that chronic loss of internal rotation secondary to posterior capsular contracture may be an explanation for refractory pain in some patients with an initial diagnosis of impingement syndrome. This condition appears to be amenable to arthroscopic posterior capsular release.