Cartilage diseases have a significant impact on the patient's quality of life and are a heavy burden for the healthcare system. Better understanding, early detection and proper follow-up could improve quality of life and reduce healthcare related costs. Therefore, the aim of this study was to evaluate if difference between osteoarthritic (OA) and non-osteoarthritic (non-OA) knees can be detected quantitatively on cartilage and subchondral bone levels with advanced but clinical available imaging techniques. Two OA (mean age = 88.3 years) and three non-OA (mean age = 51.0 years) human cadaveric knees were scanned two times. A high-resolution peripheral quantitative computed tomography (HR-pQCT) scan (XtremeCT, Scanco Medical AG, Switzerland) was performed to quantify the bone microstructure. A contrast-enhanced clinical CT scan (GE Revolution Evo, GE Medical Systems AG, Switzerland) was acquired with the contrast agent Visipaque 320 (60 ml) to measure cartilage. Subregions dividing the condyle in four parts were identified semi-automatically and the images were segmented using adaptive thresholding. Microstructural parameters of subchondral bone and cartilage thickness were quantified. The overall cartilage thickness was reduced by 0.27 mm between the OA and non-OA knees and the subchondral bone quality decreased accordingly (reduction of 33.52 % in BV/TV in the layer from 3 to 8 mm below the cartilage) for the femoral medial condyle. The largest differences were observed at the medial part of the femoral medial condyle both for cartilage and for bone parameters, corresponding to clinical observations. Subchondral bone microstructural parameters and cartilage thickness were quantified using in vivo available imaging and apparent differences between the OA and non-OA knees were detected. Those results may improve OA follow-up and diagnosis and could lead to a better understanding of OA. However, further in vivo studies are needed to validate these methods in clinical practice

Intra-articular injection is a common way to deliver biologics to joints, but their effectiveness is limited by rapid clearance from the joint space. This barrier can be overcome by genetically modifying cells within the joint such that they produce anti-arthritic gene products endogenously, thereby achieving sustained, therapeutic, intra-articular concentrations of the transgene products without re-dosing. A variety of non-viral and viral vectors have been subjected to preclinical testing to evaluate their suitability for delivering genes to joints. The first transfer of a gene to a human joint used an ex vivo protocol involving retrovirally transduced, autologous, synovial fibroblasts. Recent advances in vector technology allow in vivo delivery using adeno-associated virus (AAV). We have developed an AAV vector encoding the interleukin-1 receptor antagonist (AAV.IL-1Ra) for injection into joints with osteoarthritis (OA). It showed efficacy and safety in equine and rat models of OA, leading to a recently-completed, investigator-initiated, Phase I, dose-escalation clinical trial in 9 subjects with mid-stage OA of the knee (. ClinicalTrials.gov. Identifier: NCT02790723). Three cohorts of three subjects with mild to moderate OA in the index knee were injected intra-articularly under ultrasound guidance with a low (10e11 viral genomes) medium (10e12 viral genomes) or high (10e13 viral genomes) dose of AAV.IL-1Ra and followed for one year. The data confirm safety, with evidence of sustained intra-articular expression of IL-1Ra and a clinical response in certain subjects. Funding for a subsequent Phase Ib trial involving 50 subjects (. ClinicalTrials.gov. Identifier: NCT05835895), expected to start later this year, has been acquired. Progress in this area has stimulated commercial activity and there are now at least seven different companies developing gene therapies for OA and a number of clinical trials are in progress. Acknowledgement: Clinical trial funded by US Department of Defense Clinical Trial Award W81XWH-16-1-0540

The knee joint has also a periarticular adipose tissue, which is known as Hoffa's fat pad (IPFP). IPFP has a dual function in the joint it reduces the concentration of Nitric Oxide, the release of glycosaminoglycans and the expression of MMP1 in the cartilage, but it also contains MSC and macrophages. Our hypothesis is that synovial fluid contains elements, not all of which are understood, which act as messengers and alter the “homeostasis” of the knee and the metabolism of all the cellular components of the joint, including the MSC of Hoffa's fat pad, thus making them another piece in the puzzle as far as OA of the knee is concerned. The IPFP of 37 patients with OA and 36 patients with ACL rupture were analyzed. Isolation, primary culture, and a functional and proteomic study of MSCs from IPFP were performed. Our results show that OA of the knee, in its more severe phases, also affects the MSC's of IPFP, which is a new actor in the OA degenerative process and which can contribute to the origin, onset and progression of the disease. A differential protein profile between OA and ACL patients were identified. Infrapatellar pad should be regarded as an adipose tissue with its own characteristics and it´s also able to produce and excrete important inflammatory mediators directly into the knee joint

There is an evolving body of evidence that demonstrates the role of epigenetic mechanisms, such as DNA-methylation in the pathogenesis of OA. This systematic review aims to summarize the current evidence of DNA methylation and its influence on the pathogenesis of OA. A pre-defined protocol in alignment with the PRISMA guidelines was employed to systematically review eight bibliographic databases, to identify associations between DNA-methylation of articular chondrocytes and osteoarthritis. A search of Medline (Ovid), Embase, Web-of-Science, Scopus, PubMed, Cinahl (EBSCOhost), Cochrane Central and Google Scholar was performed between 1st January 2015 to 31st January 2021. Data extraction was performed by two independent reviewers. During the observation period, we identified 15 gene specific studies and 24 genome wide methylation analyses. The gene specific studies mostly focused on the expression of pro-inflammatory markers, such as IL8 and MMP13 which are overexpressed in OA chondrocytes. DNA hypomethylation in the promoter region resulted in overexpression, whereas hypermethylation was seen in non-OA chondrocytes. Others reported on the association between OA risk genes and the DNA methylation pattern close to RUNX2, which is an important OA signal. The genome wide methylation studies reported mostly on differentially methylated regions comparing OA chondrocytes and non-OA chondrocytes. Clustering of the regions identified genes that are involved in skeletal morphogenesis and development. Differentially methylated regions were seen in hip OA and knee OA chondrocytes, and even within different regions of an OA affected knee joint, differentially methylated regions were identified depending on the disease stage. This systematic review demonstrates the growing evidence of epigenetic mechanisms, such as DNA methylation, in the pathogenesis of OA. In recent years, there has been a focus on the interplay between OA risk genes and DNA methylation changes which revealed a reactivation of genes responsible for endochondral ossification during development. These are important findings and may help to identify eventual future therapeutic targets. However, the current body of literature is mostly showing the differences in DNA methylation of OA chondrocytes and non-OA chondrocytes, but a true longitudinal analysis demonstrating the DNA methylation changes actually happening is still not available

Knee osteoarthritis (OA) affects an estimated 250 million people worldwide, with a cure yet to be found. Consequently, there is an urgent need to improve our understanding of OA physiopathology. While knee OA has long been mostly described as a loss of cartilage thickness (CTh) and research has focused on this characteristic, the role of bone alterations is rapidly gaining in interest. Analyzing subchondral bone mineral density (sBMD) is particularly interesting because this could inform on the mechanical environment at the knee. However, there is a paucity of data on sBMD in literature mainly because of the lack of prior methods to measure this parameter. A method for 3D sBMD assessment based on computed tomography (CT) scans was recently proposed, thus allowing testing for sBMD differences in knee OA. This study aimed at comparing non-OA and medial OA knees in terms of tibial sBMD and CTh. Specifically, it was hypothesized that sBMD and CTh differ with OA. Ten knees with severe medial OA and 10 matched non-OA knees were analyzed after ethical approval (50% male; 60 ± 3 years old). The arthro-CT scans of the 20 knees were segmented using custom software to build 3D mesh models of the tibial bone and cartilage. CTh maps were obtained by calculating the distance between cartilage and bone meshes, while sBMD maps were calculated based on the intensity of the CT in the first 3mm of bone. For each knee, the average CTh and sBMD values over the entire medial and lateral compartments were calculated and used to determine the medial-to-lateral (M/L) CTh and sBMD ratios. Unpaired t-tests and receiver operating characteristic (ROC) were used for statistical analysis. The M/L sBMD ratio was significantly higher in OA compared to non-OA knees (1.14 ± 0.04 vs. 1.08 ± 0.03; p<0.01), whereas the CTh ratio was not significantly different between groups (0.70 ± 0.21 vs. 0.85 ± 0.10; p=0.06). No significant differences were found between OA and non-OA knees for the average medial CTh and sBMD (p>0.4). High classification performance was obtained for the sBMD ratio and low performance for the average sBMD in the medial compartment (areas under the ROC curve of 0.9 and 0.6, respectively). CTh ratio and medial compartment average provided medium classification performances (areas under the curve of 0.7). This study showed that sBMD differed between non-OA and severe medial OA knees and that sBMD M/L ratio was more sensitive to OA severity than CTh variables. These results brought new insights into the pathogenesis of knee OA, by supporting the idea that sBMD is altered with OA and suggesting that sBMD could play a role in disease development. Indeed, the mechanical stresses on the cartilages are related to the mechanical characteristics of the bones. Indirectly, this study also demonstrated the value of arthro-CT scans to simultaneously assess sBMD and CTh. Additional studies with larger cohorts of patients at different stages of the disease are necessary to better understand when changes in sBMD occur

Aim. Osteoarthritis (OA) is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control the expression of genes and are likely to regulate the OA transcriptome. We performed integrative genomic analyses to define methylation-gene expression relationships in osteoarthritic cartilage. Patients and Methods. Genome-wide DNA methylation profiling of articular cartilage from five patients with OA of the knee and five healthy controls was conducted using the Illumina Infinium HumanMethylation450 BeadChip (Illumina, San Diego, California). Other independent genome-wide mRNA expression profiles of articular cartilage from three patients with OA and three healthy controls were obtained from the Gene Expression Omnibus (GEO) database. Integrative pathway enrichment analysis of DNA methylation and mRNA expression profiles was performed using integrated analysis of cross-platform microarray and pathway software. Gene ontology (GO) analysis was conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Results. We identified 1265 differentially methylated genes, of which 145 are associated with significant changes in gene expression, such as DLX5, NCOR2 and AXIN2 (all p-values of both DNA methylation and mRNA expression < 0.05). Pathway enrichment analysis identified 26 OA-associated pathways, such as mitogen-activated protein kinase (MAPK) signalling pathway (p = 6.25 × 10-4), phosphatidylinositol (PI) signalling system (p = 4.38 × 10-3), hypoxia-inducible factor 1 (HIF-1) signalling pathway (p = 8.63 × 10-3 pantothenate and coenzyme A (CoA) biosynthesis (p = 0.017), ErbB signalling pathway (p = 0.024), inositol phosphate (IP) metabolism (p = 0.025), and calcium signalling pathway (p = 0.032). Conclusion. We identified a group of genes and biological pathwayswhich were significantly different in both DNA methylation and mRNA expression profiles between patients with OA and controls. These results may provide new clues for clarifying the mechanisms involved in the development of OA. Cite this article: A. He, Y. Ning, Y. Wen, Y. Cai, K. Xu, Y. Cai, J. Han, L. Liu, Y. Du, X. Liang, P. Li, Q. Fan, J. Hao, X. Wang, X. Guo, T. Ma, F. Zhang. Use of integrative epigenetic and mRNA expression analyses to identify significantly changed genes and functional pathways in osteoarthritic cartilage. Bone Joint Res 2018;7:343–350. DOI: 10.1302/2046-3758.75.BJR-2017-0284.R1

Objectives. This study looked to analyse the expression levels of microRNA-140-3p and microRNA-140-5p in synovial fluid, and their correlations to the severity of disease regarding knee osteoarthritis (OA). Methods. Knee joint synovial fluid samples were collected from 45 patients with OA of the knee (15 mild, 15 moderate and 15 severe), ten healthy volunteers, ten patients with gouty arthritis, and ten with rheumatoid arthritis. The Kellgren–Lawrence grading (KLG) was used to assess the radiological severity of knee OA, and the patients were stratified into mild (KLG < 2), moderate (KLG = 2), and severe (KLG > 2). The expression of miR-140-3p and miR-140-5p of individual samples was measured by SYBR Green quantitative polymerase chain reaction (PCR) analysis. The expression of miR-140-3p and miR-140-5p was normalised to U6 internal control using the 2. -△△CT. method. All data were processed using SPSS software. Results. Expression of both miR-140-3p and miR-140-5p was downregulated in OA synovial fluid, showing a statistical difference between the OA and non-OA group, and increased OA severity was associated with a decreased expression of miR-140-3p or miR-140-5p. The Spearman rank correlation analysis suggested that the expression of miR-140-3p or miR-140-5p was negatively correlated with OA severity. In addition, the expression of miR-140-5p was 7.4 times higher than that of miR-140-3p across all groups. Conclusion. The dysregulation of miR-140-3p and miR-140-5p in synovial fluid and their correlations with the disease severity of OA may provide an important experimental basis for OA classification, and the miR-140-3p/miR-140-5p are of great potential as biomarkers in the diagnosis and clinical management of patients with OA. Cite this article: C-M. Yin, W-C-W. Suen, S. Lin, X-M. Wu, G. Li, X-H. Pan. Dysregulation of both miR-140-3p and miR-140-5p in synovial fluid correlate with osteoarthritis severity. Bone Joint Res 2017;6:612–618. DOI: 10.1302/2046-3758.611.BJR-2017-0090.R1

OA pathophysiology has a vascular component consisting of venous stasis resulting in intraosseous hypertension and hypoxia. In response, osteoblasts change their cytokine expression, accelerating bone remodelling and cartilage breakdown consistent with OA. We have characterized circulatory kinetics in OA bone in animal models with dynamic contrast enhanced MRI (DCE-MRI) and . 18. F PET and have demonstrated venous stasis and reduced perfusion that temporally precede and spatially coincide with OA lesions. Osteoblast uptake of . 18. F is consistent with abnormal perfusion, bone remodelling, and severity of OA. Circulatory kinetics with DCE-MRI in humans with OA of the knee exhibit similar venous outflow obstruction. Venous stasis is associated with hypoxia in subchondral bone. As an example of the effects of hypoxia on OA osteoblasts, we have described upregulation of fibrinolytic peptides, but a deficiency in the upregulation of PAI-1, leading to the generation of plasmin by human OA osteoblasts exposed to hypoxia in vitro. Plasmin is a serine protease that has been shown to degrade cartilage in OA. Abnormal circulatory kinetics by DCE-MRI may be an imaging biomarker of OA. Pharmacologic modulation of venous stasis would have a salutary effect on the physicochemical microcirculation of subchondral osteoblasts and the pathophysiology of OA

Summary. The mechanical properties of porcine tibial plateau (TP) cartilage are shown to vary topographically. Low Elastic moduli (Em) were found in the positions where unicompartimental knee osteoarthritis (OA) lesions are typically expected to develop. These results suggest that there is a different response to load in these areas. Introduction. OA is one of the ten most disabling diseases in developed countries. OA of the knee, in particular, is a major cause of mobility impairment; up to 40% of the population over the age of 70 suffers from OA of the knee. It has been observed that unicompartmental knee OA occurs with very distinct and repeatable lesion patterns. It is hypothesised that these patterns are the result of differences in the material properties throughout articular cartilage. The aim of this study was to measure the mechanical properties of porcine cartilage in a whole undamaged TP. Materials and methods. A Whole Articular Surface Indentation Machine (WASIM) was used to measure material properties in whole intact articular surface. WASIM has five degrees of freedom (DOF). The vertical axis (Z) holds an indenter tied to a load cell and a high resolution laser. Five porcine TP were scanned using a high resolution laser to obtain the topography. Using a custom program, a grid of equally spaced points (6 mm) was defined. In vivo loading for daily activities occurs normal to the surface, therefore indentation was carried out on the same orientation. The normal vector for each indentation point was calculated by averaging the normal vectors of the points within the contact area at full load. The resulting vector allowed the calculation of angles, rotations and translation to obtain normal indentation of each point. Using a novel whole articular surface indentation machine (WASIM) in combination with a custom program, the TP was rotated to obtain normal indentation. Displacement controlled indentation was performed at 10 percent per second (pps) to 15% of the total cartilage thickness. Em was calculated at each indentation point by using Hertz contact theory and the Field and Swain Method. It was assumed that the initial portion of the unloading was purely elastic. Results and Conclusions. Em of 45 to 50 points throughout the TP were obtained for each knee. Results show low Em values in the anterior medial area. Additionally, it was possible to find an area in the posterior lateral section of the TP delimited with low Em values. These areas correspond to the unicompartimental knee OA lesions. These results suggest a correlation exists between the material properties of the TP and the locations of early lesions in knee OA. This correlation can partly be explained by the relationship between articular cartilage stiffiness and matrix integrity

Valgus unloader knee braces are a conservative treatment option for medial compartment knee osteoarthritis (OA). These braces are designed to reduce painful, and potentially injurious compressive loading on the damaged medial side of the joint through application of a frontal-plane abduction moment. While some patients experience improvements in pain, function, and joint loading, others see little to no benefit from bracing [1]. Previous biomechanical studies investigating the mechanical effectiveness of bracing have been limited in either their musculoskeletal detail [2] or incorporation of altered external joint moments and forces [3]. The first objective was to model the relative contributions of gait dynamics, muscle forces, and the external brace abduction moment to reducing medial compartment knee loads. The second objective was to determine what factors predict the effectiveness of the valgus unloading brace. Seventeen people with knee OA (8 Female age 54.4 +/− 4.2, BMI 30.00 +/− 4.0 kg/m. 2. , Kellgren-Lawrence range of 1–4 with med. = 3) and 20 healthy age-matched controls participated in this study which was approved by the institutional ethics review board. Subjects walked across a 20m walkway with and without a Donjoy OA Assist knee brace while marker trajectories, ground reaction forces, and lower limb electromyography were recorded. The external moment applied by the brace was estimated by multiplying the brace deformation by is pre-determined brace-stiffness. For each subject, a representative stride was selected for each brace condition. A generic musculokeletal model with two legs, a torso, and 96 muscles was modified to include subject-specific frontal plane alignment and medial and lateral contact locations [4]. Muscle forces, and tibiofemoral contact forces were estimated using static optimization [4]. We defined brace effectiveness as the difference in the peak medial contact force between the braced and the unbraced conditions. A stepwise regression analysis was performed to predict brace effectiveness based on: X-ray frontal plane alignment, medial joint space, KL grade, mass, WOMAC scores, unbraced walking speed, trunk, hip and knee joint angles and moments. The OA Assist brace reduced medial joint loading by approximately 0.1 to 0.2 BW or roughly 10%, during stance. This decrease was primarily due to the external brace abduction moment, and not changes in gait dynamics, or muscle forces. The brace effectiveness could be predicted (R. 2. =0.77) by the KL grade, and the magnitude of the hip adduction moment in early stance (unbraced). The brace was more effective for those that had larger hip adduction moments and for those with more severe OA. The valgus knee brace was found to reduce the medial joint contact force by approximately 10% as estimated using a musculoskeletal model. Bracing resulted in a greater reduction in joint contact force for those who had more severe OA while still maintaining a hip adduction moment similar to that of healthy controls

Osteoarthritis (OA) of the spine and diarthrodial joints is by far the most common cause of chronic disability in people over 50 years of age. The disease has a striking impact on quality of life and represents an enormous societal and economic cost, a burden that will increase greatly as populations age. OA is a complex condition with broad pathology. Damage to the articular cartilage is a consistent feature, accompanied by changes to the subchondral bone and synovium. Progression of the disease involves further degeneration of the articular cartilage, damage to the underlying bone and morphological changes that include subchondral bone thickening, development of cysts, osteophytes and inflammation of the synovium. Enhanced production of proinflammatory cytokines and matrix metalloproteinases accelerates degradation of the articular cartilage. It is striking that no approved pharmacological intervention, biological therapy or procedure prevents the progressive destruction of the OA joint. All current treatments, without exception, produce symptomatic rather than regenerative results. While there have been some exciting developments in the search for OA treatments in the last decade, including matrix metalloproteinase inhibitors, anti-TNF and anti-IL1 drugs for example, none of these has to date emerged as an effective medicinal product. There is thus an urgent and compelling need to identify, validate and test new biological therapeutics. Stromal cell therapy represents one such compelling approach. The results from several early clinical studies have indicated that this approach holds a great deal of promise for the treatment of OA. Most studies have involved direct intraarticular injection of a suspension of mesenchymal stromal cells (MSCs) for treatment of knee OA. Results from a number of controlled patient studies have suggested that this treatment results in an effective repair response. Although data regarding mechanism of action are limited, it appears that the cells have an anti-inflammatory effect, possibly targeting cells within the synovium, rather than a direct cartilage repair effect. Several recent reports have highlighted a dramatic and sustained response in patients receiving MSC treatment. For example, allogeneic expanded adipose-derived MSCs have been shown to be safe and effective in the treatment of complex perianal fistulas in Crohn's disease. Also, allogeneic bone marrow-derived MSCs has a been shown to have a positive effect in pediatric acute graft versus host disease. These observations point to a mechanism of action that involves host immunomodulation, but this needs further examination. Within the field of musculoskeletal disease effective translation of MSC technology has been hindered by a lack of randomized controlled patient studies, severe inconsistencies regarding the preparation and characterization of the cell product, and an incomplete understanding of the therapeutic mechanism. Direct to consumer clinics have flourished in some countries, providing cell treatments to OA patients. Most or all of these utilize unexpanded cell fractions from marrow or fat without even rudimentary product characterization and may report an exaggerated clinical outcome. Data from these clinics is not likely to yield information that will be useful. In fact, a recent systemic review of clinical trials involving MSC treatment in OA indicated that only a limited number of studies provided high quality evidence and long term follow up. Many suffered from a lack of consistency, including a diversity of methods for MSC preparation, and thus did not contribute to a supporting evidence base. There is a compelling need to provide clear and unambiguous clinical proof of concept relating to MSC treatment for OA. The ADIPOA2 study, currently active in Europe, will go some way towards achieving this. This is a 150 patient, phase 2b study designed to to assess the efficacy of a single injection of autologous adipose-derived MSCs in the treatment of mild to moderate OA of the knee, active and unresponsive to conservative therapy for at least 12 months

Summary. Anatomical variations in hip joint anatomy are associated with both the presence and location of tibiofemoral osteoarthritis (OA). Introduction. Variations in hip joint anatomy can alter the moment-generating capacity of the hip abductor muscles, possibly leading to changes in the magnitude and direction of ground reaction force and altered loading at the knee. Through analysis of full-limb anteroposterior radiographs, this study explored the hypothesis that knees with lateral and medial knee OA demonstrate hip geometry that differs from that of control knees without OA. Patients and Methods. This cross-sectional study is an ancillary to the Multicenter Osteoarthritis Study (MOST), an observational cohort study of incident and progressive knee OA in community-dwelling men and women, ages 50–79 years. We report on 160 knees with lateral OA (LOA), 168 knees with medial OA (MOA), and 336 controls. All participants with LOA at the baseline MOST visit were included. An equal number of knees with MOA, and twice the number of control knees were then randomly selected. In participants with bilateral eligibility, a single knee was randomly selected so that all participants contributed only one case or one control knee to the analysis. Case knees were identified as having Kellgren/Lawrence (K/L) ≥ 2 with joint space narrowing (JSN) ≥ 1 in the specified compartment with no JSN in the adjoining compartment. Controls had no radiographic OA (K/L=0 or 1 and JSN=0) in either compartment. Hip joint anatomy parameters were assessed from full-limb standing radiographs using custom OsiriX software by an author (AB) blinded to knee OA status, and unreadable radiographs (N = 8) were discarded prior to unblinding. We measured parameters that influence the abductor moment arm of the hip, including: abductor lever arm, femoral offset, femoral neck length, femoral neck-shaft angle, height of hip centre, body weight lever arm, acetabular version, and abductor angle. All hip measurements were taken from the ipsilateral side of the knee in interest. Each variable was then compared independently among the three groups via analysis of covariance (ANCOVA), controlling for age, sex, and body mass index (BMI), and followed up with a post-hoc Bonferroni analysis to distinguish pairwise group differences. Results. The ANCOVA analysis showed a significant difference in height of hip centre (p=0.001), femoral neck-shaft angle (p=0.009), and abductor angle (p=0.001). Compared to controls, knees with LOA had an increased height of hip centre (p=0.001) and knees with MOA had a decreased abductor angle (p=0.046). Compared to knees with MOA, those with LOA had a more valgus neck-shaft angle (p=0.007) and increased abductor angle (p=0.001). Conclusion. Our study demonstrates that variations in hip geometry that affect the moment-generating capacity of the hip abductors are associated with the presence and compartmental distribution of tibiofemoral OA in the ipsilateral knee. Anatomical arrangements that reduce the hip abductor moment arm are more strongly associated with LOA than with MOA

To assess the outcome of Offloading Knee brace (V-VAS) in the treatment of osteoarthritis of the knee. A total of 147 patients with knee arthritis were included in this study. Eighty six patients were followed up retrospectively and 61 patients were followed up prospectively. Average follow up was about 3.4 years in retrospective group and 1.2 years in prospective group. The Oxford knee score, Pain score, Walking distance and Patient satisfaction were evaluated. Average oxford scores before the brace was 19 and after the brace was 32. The pain scores before and after the brace was 8 and 3 respectively. The walking distance had improved to 900 yards. The patient satisfaction was 78%. Thirteen of eighty six patients in the retrospective group discontinued the brace, of these two had high tibial osteotomy, six patients had total knee replacement, one had unicondylar knee replacement, one patient had dislocation of patella and two elderly patients were house-bound because of medical problems. The Off loading knee brace is effective in the management of osteoarthritis of the knee. Patient satisfaction is high when using the brace. However compliance may be an issue in some of the patients. Education and early appointment for brace re-fitting increases patient compliance. Bracing is a beneficial treatment for severe medial OA of the knee

Osteoarthritis (OA), characterised by pain, disability and joint degeneration, is common and has no cure. Prevalence of severe radiographic knee OA is 19% in over 45's and 50% in over 75's in the US and Europe. Abnormal joint loading, or injury, increase risk of OA. We have discovered that glutamatergic signalling is mechanically regulated and glutamate receptors (GluR) drive inflammation, degeneration and pain representing potential drug targets in osteoarthritic joints. Joints from OA and knee injured patients, and rodent models of arthritis, show increased synovial fluid glutamate concentrations and abundant GluR expression. Since AMPA/kainate GluRs regulate IL-6, a critical mediator of arthritic degeneration, we tested protective effects of the AMPA/KA GluR antagonist, NBQX in animal models of arthritis. In rodent antigen induced arthritis, and osteoarthritis (meniscal transection and anterior cruciate ligament rupture), NBQX reduced joint swelling, degeneration and pain, exceeding anti-degenerative effects of other drugs tested similarly. 3D osteocyte/osteoblast co-cultures and human bone samples taken from patients undergoing high tibial osteotomy joint realignment surgery, revealed underlying cellular mechanisms mediated by bone cells. Related drugs, already used in humans for epilepsy and migraine, represent a repurposing opportunity and are effective in our models of arthritis

Although osteoarthritis (OA) is characterized by articular cartilage damage, synovial inflammation is a prominent feature contributing to disease progression. In addition to synovial tissue resident macrophages, infiltrating macrophages and monocytes, their lineage precursors, may also contribute to pathological processes. In mice, peripheral blood monocytes may be categorized according to pro-inflammatory/classical and patrolling/non-classical subsets. The aim of this study was to identify profiles of peripheral blood monocyte subsets as well as different synovial macrophage phenotypes during disease development. OA was induced in knees of C57BL/6 mice by destabilization of the medial meniscus (DMM). Blood was harvested from the facial vein 7 days prior to and 1, 7, 14, 28, and 56 days post induction of OA. Separate mice were sham-operated as a control. Monocyte subsets and synovial macrophage populations were identified by flow cytometry. Levels of classical monocytes were significantly higher at day 14 (p<0.001) and day 28 (p=0.031) in peripheral blood of DMM-operated mice compared to control. Furthermore, the percentage of non-classical monocytes was significantly lower in DMM-mice at day 14 (p=0.026). At day 56 post OA-induction, an increase in total synovial macrophages (CD11b+F4/80+ cells) was observed between DMM and sham operated knees (p=0.021). The ratio between pro-inflammatory (CD11b+F4/80+CD86+) and tissue repair (CD11b+F4/80+CD206+) synovial macrophage subsets tended to be higher in DMM knees, however this finding was not statistically significant (p>0.05). In light of the present findings, further investigation is required to elucidate the relationship of peripheral blood monocyte subsets to synovial inflammation and features of OA pathogenesis

The benefits of surgical treatments for osteoarthritis (OA) of the knee are well established. There are also advances in non-surgical management techniques that can be used successfully, and these may be particularly suitable for patients with mild to moderate disease, or for those in whom surgery is contra-indicated. Intra-articular viscosupplementation is one such method, and studies have shown that this can give short-term symptomatic relief. Our study looked at the patient perceived benefits of a course of Hylan G-F 20 (Synvisc¯) by comparing the modified Brief Pain Inventory short form (BPI-sf) scores before treatment and after three months. The BPI-sf is a validated, widely used, self-administered questionnaire that measures both sensory and reactive dimensions of the pain using scales of 0-10 or 0-100%. This study included 12 consecutive patients with OA of the knee treated with a course of three Synvisc¯ injections performed a week apart. The data were treated as non-parametric and therefore Wilcoxon signed rank tests were performed. The data are presented as median (IQR). The results showed statistically significant (p<0.05), and clinically significant (reduction >1 point) improvements in worst, best, and average pain scores (over the previous 24 hours) three months following treatment compared to those before treatment. Relief obtained from routinely taken analgesia was significantly improved from 30%(12.5-57.5) to 75%(42.5-100) (p=0.009) following treatment. There were significant reductions in the interference of the pain with: general activity from 6(4.25-8.75) to 2.5(0-6.75), (p=0.006); mood from 6(2-8) to 0(0-5), (p=0.004); walking ability from 7.5(4-8.75) to 3.5(0.25-6), (p=0.004); normal work from 5.5(3.5-8) to 1.5(0-5), (p=0.009); relations with other people from 4(2-8) to 0(0-3.5), (p=0.006); sleep from 6(3.25-9.5) to 1.5(0-5.75), (p=0.004); enjoyment of life from 6(2.75-8.5) to 1.5(0-6), (p=0.005). All patients found the treatment acceptable. We conclude that patients reported significant improvements in pain, physical and emotional functioning, and sleep three months following treatment with this viscosupplementation treatment

Summary Statement. We observed that severe muscle weakness leads to OA, whereas a transient inflammatory stimulus did not have a significant effect on cartilage degradation. This arises the thought that a severe but transient inflammation may not be an independent risk factor for OA. Introduction. Biomechanical disturbances and joint inflammation are known risk factors, which may provoke or advance osteoarthritis (OA). However, the effect of interactions of such risk factors on the onset and progression of OA are still poorly understood. Therefore, the goal of this study was to investigate the in vivo effects of muscle weakness, joint inflammation, and the combination of these two risk factors, on the onset and progression of OA in the rabbit knee. Patients & Methods. Thirty 1-year-old skeletally mature female New Zealand White rabbits (weight: average 5.7kg, range 4.8–6.6kg) were used in this study. The animals were divided into four experimental groups: (i) surgical transection of the nerve branch of the common femoral nerve leading to the vastus lateralis muscle; (ii) muscle weakness of the quadriceps muscle induced by a chronic intramuscular injection of Botulinum toxin A (BTX-A) (3); (iii) intraarticular injection in the experimental knee joint with commercially available sterile Carrageenan solution to induce a transient severe inflammatory reaction (4); (iv) administration of both intraarticular injection of Carrageenan and intramuscular injection of BTX-A. In each animal, one hind limb was randomly assigned to the experimental intervention, while the contralateral side acted as its own control. Ninety days following intervention, muscle mass, joint diameter and cartilage histology of the femur, femoral groove, tibia and patella were assessed and microscopically analyzed using the OARSI histology score. Results. Transection of the femoral branch leading to the vastus lateralis as well as the administration of BTX-A led to a significant muscle mass loss for the vastus lateralis and the total quadriceps group, respectively. Similar results were seen in the combined Carrageenan/BTX-A group. There were no changes in total quadriceps muscle mass in the Carrageenan group. Knee joint diameters of the experimental limb were significantly increased in the Carrageenan and Carrageenan/BTX groups. VL transection and BTX-A injection did not cause significant increases in joint diameter. Histologic assessment of the cartilage showed that weakness of the vastus lateralis resulted in significantly higher OARSI scores in the patella and femoral groove, but not the tibiofemoral articulation. The administration of BTX-A caused significant cartilage damage in all 4 compartments (patella, femur, tibia, femoral groove). Intraarticular injection of Carrageenan did not cause significant cartilage damage in any compartment compared to the contralateral side. The combination of BTX-A and Carrageenan resulted in severe cartilage damage in the patella in all four compartments of the knee. The most severe damage was found on the medial side of the tibiofemoral joint and the lateral side of the patellofemoral joint. Conclusion. Severe muscle weakness over a three months period leads to the onset and progression of OA in the rabbit knee. A transient local inflammatory stimulus did not promote cartilage degradation, nor did it enhance cartilage degradation when it was combined with muscle weakness. This result is surprising and adds to the literature the idea that a severe but transient inflammation may not be an independent risk factor for OA

Introduction. Osteoarthritis (OA) of the knee, a prevalently degenerative joint disorder provoked by articular cartilage loss, accounts for the leading cause of total knee arthroplasty. Autophagy is an indispensable intracellular event that maintains chondrocyte survival and metabolism. MicroRNAs are non-coding small RNAs participating in tissue morphogenesis, remodeling, and homeostasis. This study was undertaken to investigate the effect of microRNA-128 (miR-128) knockdown on the development of OA knees. Materials/Methods. Knee joints in rats were subjected to anterior cruciate ligament transection (ACLT) for inducing OA. Articular cartilage, synovium, and subchondral bone microarchitecture were assessed by OARSI scoring system, histomorphometry, and μCT imaging. Chondrocyte autophagy in terms of the expression of autophagic markers Atg4, Atg12, microtubule-associated protein 1 light chain 3 (LC3), and autophagosome formation was verified. Expression of microRNA, mRNA and signaling transduction were quantified with in situ hybridization, RT- quantitative PCR, and immunoblotting. Results. Chondrocytes in the affected knees showed weak expression of autophagic markers Atg4, Atg12, and LC3-II abundances in conjunction with significant increases in OARSI scores and a 2.5-fold elevation in miR-128 expression. The gain of miR-128 signaling in intact joints through intra-articular injection of miR-128 precursor resulted in 1.8–2.1-fold elevations in serum cartilage breakdown products CTX-II and COMP concentrations. miR-128 overexpression caused the joints to show evident chondrocyte apoptosis as evidenced by TUNEL staining concomitant with severe cartilage damage. Of note, antisense oligonucleotide knockdown of miR-128 (miR-128-AS) enabled the affected knee joints to show minor responses to the ACLT escalation of autophagy dysfunction in chondrocytes, cartilage breakdown histopathology, and OARSI scores. Administration with miR-128-AS also attenuated the ACLT-induced synovial membrane thickening, hyper-angiogenesis, and hypercellularity, which subsequently alleviated osteophyte accumulation, subchondral plate destruction, and trabecular microstructure loss. Conclusion. miR-128 signaling impairs chondrocyte autophagy, which ramps up chondrocyte apoptosis and OA knee development. This study highlights an emerging miR-128 knockdown strategy that sustains cartilage microarchitecture integrity and thereby delays OA knee pathogenesis

Introduction. Patients with knee osteoarthritis (OA) often tell us that they put extra load on the joints of the opposite leg as they walk. Multiple joint OA is common and has previously been related to gait changes due to hip OA (Shakoor et al 2002). The aim of this study was to determine whether patients with medial compartment knee OA have abnormal biomechanics of the unaffected knee and both hips during normal level gait. Methods. Twenty patients (11 male, 9 female), with severe medial compartment knee OA and no other joint pain were recruited. The control group comprised 20 adults without musculoskeletal pain. Patients were reviewed, x-rays were examined and WOMAC and Oxford knee scores were completed. A 12 camera Vicon (Vicon, Oxford) system was used to collect kinematic data (100Hz) on level walking and the ground reaction force was recorded using three AMTI force plates (1000Hz). Surface electrodes were placed over medial and lateral quadriceps and hamstrings bilaterally to record EMG data (1000Hz). Kinematics and kinetics were calculated using the Vicon ‘plug-in-gait’ model. A co-contraction index was calculated for the EMG signals on each side of the knee, representing the magnitude of the combined readings relative to their maximum contraction during the gait cycle. Statistical comparisons were performed using t-tests with Bonferroni's correction for two variables and ANOVA for more than two variables (SPSS v16). Results. The mean age of the patients was 69 (SD 8.8). Mean gait speed was 0.95m/s (study group) and 1.44m/s (control group). Peak adduction moments for the OA group [OA Knee; Unaffected Knee; Ipsilateral Hip; Contralateral Hip; in Nm/Kg(±95% CI)] were: 0.55(0.06); 0.47(0.06); 0.73(0.09); 0.73(0.08). Control values for peak moments were 0.64 (0.06) for the knee and 0.81(0.07) at the hip. Mid-stance adduction moments for the OA group (listed as before) were: 0.44(0.08); 0.33(0.06); 0.64(0.06); 0.61(0.08). Control values for mid-stance moments were 0.14(0.03) and 0.40(0.04). [OA group vs. Controls: p=NS for peak moments at all 4 joints; p<0.01 for mid-stance moments at all joints]. Co-contraction indices for hamstrings and quads, [OA knee medial; and lateral; unaffected knee medial; and lateral; control medial; and lateral; 0<X. Discussion. Although the affected subjects all had only single joint OA, abnormal moments were present in the hips and knees of both legs during normal level gait, despite the reduced gait speed of the OA cohort. Abnormal hamstring and quadriceps co-contraction occurs bilaterally in patient with single joint OA. Increased trunk sway is a recognised compensation in knee OA and may be the cause of the abnormal hip and contra-lateral knee loading found in this study. Further investigation is warranted and may lead to improvements in the long term outcome for these patients. Acknowledgement. The study was funded by the North Wales NHS Trust

Background. Epigenetic regulation of gene transcription affects metabolism of chondrocytes and synovial fibroblasts and is associated with the prevalence of osteoarthritis (OA) of knees. Histone lysine demethylase (KDMs) reportedly modulates tissue homeostasis and deterioration. This study investigated whether KMD6a inhibitor treatment affected the joint injuries in the progression of OA. Methods. Collagenase-induced OA knees in mice were intra-articular administered with KDM6a inhibitor GSK-J4. Walking patterns and footprints of affected animals were detected by Catwalk. Articular cartilage injury was quantified by OARSI scoring; and subchondral bone microstructure was analysed by μCT imaging. Histopathology and mRNA expression of cartilage, fibrosis and bone matrices in joint micro-compartments were detected by histomorphometry and quantitative RT-PCR. Methylation states of chondrogenic transcription factor SOX9 promoter was detected by methylation-specific PCR and chromatin immuno-precipitation. Results. Declined KDM6a expression and SOX9 gene transcription was associated with the pathogenesis of collagenase-induced joint injures. GSK-J4 administration dose-dependently improved gait profiles and footprint characteristics of affected feet and alleviated histopathology of severe cartilage degradation, synovial inflammation, fibrotic matrix accumulation and subchondral bone microarchitecture deterioration in injured joints. Treatment with GSK-J4 decreased expression of fibrogenic factor (TGF-β1, PLOD2 and TIMP) and restored expression of cartilage and bone matrices (collagen II, I, aggrecan, and osteocalcin). KDM6a inhibitor curtailed the hypomethylation of SOX9 promoter and lysine 27 of histone H3 (H3K27) and restored SOX9 mRNA and protein levels in joint tissues. Conclusions. KDM6a enhanced SOX9 promoter and H3K27 hypomethylation that accelerated the progression of OA. KDM6a inhibitor had mitigated effects on SOX9 promoter demethylation thereby restored SOX9 signaling and stabilised homeostasis of cartilage, synovium and subchondral bone compartments in affected joints. This study sheds a new light on the KDM6a-mediated epigenetic dysfunction in OA joints and has a perspective that pharmaceutical KDM6a inhibitor has therapeutic potential for OA knee pathogenesis. Level of evidence. II