Aims. Animal models have been developed that allow simulation of post-traumatic joint contracture. One such model involves contracture-forming surgery followed by surgical capsular release. This model allows testing of antifibrotic agents, such as rosiglitazone. Methods. A total of 20 rabbits underwent contracture-forming surgery. Eight weeks later, the animals underwent a surgical capsular release. Ten animals received rosiglitazone (intramuscular initially, then orally). The animals were sacrificed following 16 weeks of free cage mobilisation. The joints were tested biomechanically, and the posterior capsule was assessed histologically and via genetic microarray analysis. Results. There was no significant difference in post-traumatic contracture between the rosiglitazone and control groups (33° (standard deviation (. sd. ) 11) vs 37° (. sd. 14), respectively; p = 0.4). There was no difference in number or percentage of myofibroblasts. Importantly, there were ten genes and 17 pathways that were significantly modulated by rosiglitazone in the posterior capsule. Discussion. Rosiglitazone significantly altered the genetic expression of the posterior capsular tissue in a rabbit model, with ten genes and 17 pathways demonstrating significant modulation. However, there was no significant effect on biomechanical or histological properties. Cite this article: M. P. Abdel. Effectiveness of rosiglitazone in reducing flexion contracture in a rabbit model of arthrofibrosis with surgical capsular release: A biomechanical, histological, and genetic analysis. Bone Joint Res 2016;5:11–17. doi: 10.1302/2046-3758.51.2000593

Dupuytren's disease (DD) is a fibroproliferative soft tissue disease affecting the palmar fascia of the hand causing permanent and irreversible flexion contracture. Aberrant fibrosis is likely to manifest through a combination of extrinsic, intrinsic, and environmental factors, including genetics and epigenetics. However, the role of epigenetics in soft tissue fibrosis in diseases such as DD is not well established. Therefore, we conducted a comprehensive multi-omic study investigating the epigenetic profiles that influence gene expression in DD pathology. Using control (patients undergoing carpal tunnel release) and diseased fibroblasts (patients undergoing Dupuytren's fasciectomy), we conducted ATAC-seq to assess differential chromatin accessibility between control and diseased fibroblasts. Additionally, ChIP-seq mapped common histone modifications (histone H4; H3K4me3, H3K9me3, H3K27me3, H4K16Ac, H4K20Me3) associated with fibrosis. Furthermore, we extracted RNA from control and DD tissue and performed bulk RNA-seq. ATAC-seq analysis identified 2470 accessible genomic loci significantly more accessible in diseased fibroblasts compared to control. Comparison between diseased and control cells identified numerous significantly different peaks in histone modifications (H4K20me3, H3K27me3, H3K9me3) associated with gene repression in control cells but not in diseased cells. Pathway analysis demonstrated a substantial overlap in genes being de-repressed across these histone modifications (Figure 1). Both, ATAC-seq and ChIP-seq analysis indicated pathways such as cell adhesion, differentiation, and extracellular matrix organisation were dysregulated as a result of epigenetic changes. Moreover, de novo motif enrichment analysis identified transcription factors that possibly contributed to the differential gene expression between control and diseased tissue, including HIC1, NFATC1 and TEAD2. RNA-seq analysis found that these transcription factors were upregulated in DD tissue compared to control tissue. The current epigenetic study provides insights into the aberrant fibrotic processes associated with soft tissue diseases such as DD and indicates that epigenetic-targeted therapies may be an interesting viable treatment option in future. For any figures or tables, please contact the authors directly

Dupuytren Disease (DD), the most common connective tissue disease in man, presents as a benign fibromatosis of the hands and fingers resulting in the formation of nodules and cords and often leading to flexion contractures in association with keloids or Peyronie disease. Surgical resection of the fibrotic nodules, and more recently intra-lesional collagenase injection are the main therapeutic options for these patients. While the exact cause of DD is still unknown, linkage and Genome Wide Association Studies (GWAS) showed molecular heterogeneity with at least 10 different susceptibility loci 6 of which are close to genes encoding proteins in the Wnt-signaling pathway. We aim to identify the molecular basis of Dupuytren Disease (DD). Twenty patients with Dupuytren disease (including 3 patients with autosomal dominant inheritance, 1 with keloids and congenital torticollis, 2 with Peronie disease), were included in this study. Chromosome Microarray Analysis (CMA), Whole Exome Sequencing (WES) of gDNA and proteomic analysis by LC-Tandem Mass Spectrometry (LC-MSMS) studies were performed. Expression and Network analysis of LCMSMS results was performed using Principal Component Analysis (PCA), ANOVA and Ingenuity Pathway Analysis (IPA). No pathogenic copy number variants (CNVs) were found in CMA (n = 3). WES showed potentially pathogenic variants in POSTN, WNT11, MMP1 and COL3A1. PCA showed three differentially expressed clusters and network-IPA identified ACTB, BAX, COL3A1, FBN1, FN1, MMP1 as potential biomarkers. Comprehensive multi-OMIC analysis of gDNA and tissue proteins in patients with DD identified several connective tissue biomarkers potentially important in the pathogenesis of DD

Fixed flexion contracture (FFC) following total knee arthroplasty (TKA) is a source of morbidity for patients. This retrospective review of pre- and post-operative data for 811 total knee replacements with two year follow up aimed to identify pre-operative risk factors for developing FFC and quantify the effect of FFC on outcomes. The incidence of FFC two years post-operation was 3.6%. Advanced age was associated with increased rate of FFC (p=0.02) Males were 2.6 times more likely than females to have FFC at two years (p=0.012). Patients with pre-implant FFC were 2.95 times more likely than those without to have FFC (p=0.028). BMI was not a risk factor (p=0.968). Patients with FFC had poorer outcomes (Oxford Knee Score p=0.003, patient satisfaction p=0.036). The results of this study support the existing literature and clarify a previously contentious point by excluding BMI as a risk factor

Distal femur resection for correction of flexion contractures in total knee arthroplasty (TKA) can lead to joint line elevation, abnormal knee kinematics and patellofemoral problems. The aim of this retrospective study was to establish the contribution of soft tissue releases and bony cuts in the change in maximum knee extension in TKA. Data were available for 211 TKAs performed by a single surgeon using a medial approach. Intra-operatively pre- and post-implant extension angles and the size of bone resection were collected using a commercial navigation system. The thickness of polyethylene insert and the extent of soft tissue release performed (no release, moderate and extensive release) were collected from the patient record. A linear model was used to predict change in maximum extension from pre- to post-implant. The analysis showed that bone cuts (p<0.001), soft tissue release (p=0.001) and insert thickness (p=0.010) were all significant terms in the model (r. 2. adj. =0.170). This model predicted that carrying out a TKA with 19 mm bone cuts, 10 mm insert and no soft tissue release would give 4.2° increase in extension. It predicted that a moderate release would give a further 2.8° increase in extension with an extensive release giving 3.9°. For each mm increase in bone cuts the model predicted an 0.8° increase in extension and for each mm increase in insert size a decrease extension by 1.1°. The modelling results show that in general to increase maximum extension by the same as an extensive soft tissue release that bone cuts would have to be increased by 4–5 mm. However this model only accounted for 17% of the variation in change in extension pre- to post-implant so may not be accurate at predicting outcomes for specific patients

Summary. Based upon genetic analysis, decorin is an exciting pharmacologic agent of potential anti-fibrogenic effect on arthrofibrosis in our animal model. Introduction. While the pathophysiology of arthrofibrosis is not fully understood, some anti-fibrotic molecules such as decorin could potentially be used for the prevention or treatment of joint stiffness. The goal of this study was to determine whether intra-articular administration of decorin influences the expression of genes involved in the fibrotic cascade ultimately leading to less contracture in an animal model. Material and Methods. Eighteen rabbits had their right knees operated on to form contractures. The left knees served as controls. The 6 right limbs in the experimental group (Group 1) received four 500 ug/ml intra-articular injections of decorin over 8 days starting at 8 week, for a total of 2 mg. The 6 right limbs in the first control group (Group 2) received four intra-articular injections of bovine serum albumin (BSA) over 8 days starting at 8 weeks as well. The 6 six right limbs in the second control group (Group 3) received no injections. The contracted limbs of rabbits in Group 1 were biomechanically and genetically compared to the contracted limbs of rabbits in Groups 2 and 3 with the use of a calibrated joint measuring device and custom microarray, respectively. Results. There was no statistical difference in the flexion contracture angles between those right limbs that received intra-articular decorin versus those that received intra-articular BSA (66° vs. 69°; p = 0.41). Likewise, there was no statistical difference between those right limbs that received intra-articular decorin as opposed to those who had no injection (66° vs. 72°; p = 0.27). The lack of significance remained when the control left limbs were taken into account (p > 0.40). When compared to bovine serum albumin (BSA), decorin led to a statistically significant increase in the mRNA expression of 5 genes: substance P, neuropeptide γ, and neurokinin A, cyclin E2, and MMP-9 (p < 0.001). In addition, there was a statistically significant decrease in fibroblast growth factor receptor-2 (FGFR-2), rho-associated coiled-coil containing protein kinase-1 (ROCK-1), and vascular cell adhesion molecule-1 (VCAM-1) genes when intra-articular decorin was compared to no injection (p < 0.001). Conclusions. In this model, when administered intra-articularly at 8 weeks, 2 mg of decorin had no significant effect on joint contractures. However, our genetic analysis revealed a significant alteration in the expression of several fibrotic genes. Further studies investigating the route of administration, dosing, frequency, and timing are required before definitive conclusions may be drawn on the effects of decorin on joint contractures

Summary Statement. We present a simple and useful geometrical equation system to carry out the pre-operative planning and intra-operative assessments for total knee arthroplasty. These methods are extremely helpful in severely deformed lower limbs. Introduction. Total knee arthroplasty is a highly successful surgery for most of the patients with knee osteoarthritis. With commercial instruments and jigs, most surgeons can correct the deformity and provided satisfactory results. However, in cases with severe extra-articular deformity, the instruments may mislead surgeons in making judgment of the true mechanical axis. We developed a geometrical equation system for pre-operative planning and intra-operative measurement to perform correct bony cuts and achieve good post-operative axis. Patients & Methods. From 2008 to 2012, twenty-four patients with severe extra-articular deformities of low limbs underwent total knee arthroplasties for osteoarthritis. The deformities included malunion of femoral or tibial shafts with angulation, non-union of femoral supracondylar fractures, failed high tibia osteotomies, severe bowing of femurs, and other post-traumatic sequelae. The intra-medullary or extra-medullary guide devices were not possible to provide correct axis in these cases. For pre-operative planning, we analyzed the deformities on triple-film scanography and standing anterior-posterior and lateral X-ray films. The angles needed to be corrected in coronal and sagittal planes were measured. A geometrical equation system was applied to calculate the thickness of the proximal tibia cut and distal femoral cut. If the flexion contracture was presented, the degree of necessary elevation of joint line was also calculated. Intra-operatively, the degree of rotation of anterior and posterior femoral cuts was assessed after proximal tibial and distal femoral cuts. The sizes of prosthesis were judged according to the balance between flexion and extension gaps. A 3-in-1 jig was used for chamfering of the femur. After fine-tuning of bony cuts and balancing of soft tissue, the prostheses were cemented. The conventional intra-medullary and extra-medullary guiding devices were not used during the whole procedure. Results. All of the patients achieved satisfactory results in the aspect of pain relief and functional outcomes. All patients had good post-operative axis in coronal plane (varus or valgus deformity < 3 degrees). Twenty-two patients (92%) achieved good sagittal alignments (deformity < 3 degrees). The results were compatible with those in the patient population without those severe deformities. There was no major complication among these patients. Discussion/Conclusion. In this series, we present a simple and useful geometrical equation system to carry out the pre-operative planning and intra-operative assessments for total knee arthroplasty. These methods are extremely helpful in severely deformed lower limbs. Optimal post-operative alignments were achieved in this series and no major complication was found