Joint load reduction is effective for alleviating OA pain. Treatment options for joint unloading include braces and HTO, both of which may be impractical for patients. The purpose of the present study was to examine the biomechanical rationale of a practical, partial unloading implant (KineSpring® System, Moximed) for knee OA.

Device durability was tested by cyclically loading bone-implant constructs through simulated use for at least 10 million cycles. Joint load reduction with the implant was quantified by measuring changes in medial and lateral knee compartment loads generated by cadaver knees in simulated gait. Safety of the device was tested by 3, 6, and 12 month follow-up of implants in an in vivo ovine model. Surgical technique and device safety and efficacy were assessed in human clinical studies.

The unloader device survived over 15 million cycles of simulated use without failure. In the simulated gait cadaver model, the unloading device significantly reduced medial compartment (29 ± 13 lbs, p<0.05) and overall knee joint loads during the stance phase of gait testing but did not significantly increase lateral compartment loading. Chronic ovine implants demonstrated good tolerance of the implant with normal wound healing and secure device fixation. Clinical experience (n=49) demonstrated uneventful device implantation. Unlike HTO, the implantation technique for the unloader does not alter joint alignment. This surgical technique avoids removal of bone, ligament, and cartilage, thus preserving future primary arthroplasty, if required. Early-term clinical experience also demonstrates good outcomes for patients, the earliest of whom are beyond 2.6 years with the implant.

This unloading device offers a practical and attractive treatment option for patients with medial knee OA: load reduction without load transfer, durability, preservation of downstream treatment options, safety, and early-term efficacy.

Opening wedge high tibial osteotomy (OWHTO) is a treatment option for medial compartment osteoarthritis of the knee in the young active adult. Limited evidence exists in the literature regarding return to activities following OWHTO.

We performed a retrospective study of local patients who underwent OWHTO from 2005 – 2012 assessing post-operative return to sporting function. Patients with additional knee pathology, surgery or alternative issues affecting activity were excluded.

110 patients met inclusion criteria, 75 were successfully contacted.

Mean improvement in pain score = 4.8/10 (95%CI 4.2 to 5.4, p<0.01). Mean pre-operative KOS-SAS score = 0.5/2, mean post-operative KOS-SAS score = 1.1/2, mean change in KOS-SAS score following OWHTO = 0.6 (95% CI 0.5 to 0.7, p<0.01). Mean pre-morbid Tegner score = 5.9/10, pre-operative = 2.7/10, post-operative = 4.2/10. Mean change in Tegner score following OWHTO = 1.5 (95% CI 1 to 1.9, p<0.01). Following OWHTO 25% of patients achieved pre-morbid Tegner scores. Patient BMI, age, type of implant or graft used had no significant effect on outcome.

OWHTO can temporarily improve pain, activity and sporting levels in young patients with isolated medial compartment knee OA. Return to pre-morbid activity levels and even high level sports function is possible although not the norm.

Aims

Unicompartmental knee arthroplasty (UKA) is the preferred treatment for anterior medial knee osteoarthritis (OA) owing to the rapid postoperative recovery. However, the risk factors for UKA failure remain controversial.

The management of disabling osteoarthritis of the knee following ipsilateral femoral fracture malunion can be difficult. This study presents the results of seven such patients treated by femoral shaft osteotomy in the fracture region and with locked intramedullary nail fixation.

Seven patients with malunited femoral shaft fractures presenting with knee symptoms between 1992 and 1999 were treated by femoral shaft osteotomy. The presenting knee symptoms and function were graded from 0–4. All patients underwent open femoral shaft osteotomy at the apex of the deformity and fixation was by locked intramedullary nailing. The patients were followed up until osteotomy union and reviewed clinically and radiologically with particular emphasis on knee symptoms and function.

There were six males and one female. The mean age at presentation was 48 years and the mean time from fracture 28 years. (Range 13–37 years). The mean knee alignment angle preoperatively was 5 degrees varus (range 0–12). The mean time to osteotomy union was 28 months. The mean knee alignment angle postoperatively was 2 degrees valgus. (range 5 degrees varus-5 degrees valgus). Five of the seven patients reported excellent pain relief and functional improvement. One patient had serious vascular complication and now has a stiff but pain free knee. One patient who presented with very advanced OA has since undergone an uncomplicated total knee arthroplasty after osteotomy union and nail removal.

These patients presenting with severe disability at an age that would be too young for total knee replacement are difficult to manage. Five out seven patients in these series are symptomatically improved to return to their old occupation. The knee replacement has been delayed in these by a mean of five years. Their eventual knee replacement is likely to have been made less difficult as a result of alignment correction.

Purpose: The management of disabling knee osteoarthritis of the knee following malunion of an ipsilateral femoral shaft fracture is difficult and controversial. The purpose of this study is to analyse the results of femoral shaft osteotomy at the level of the old fracture in seven such patients.

Materials and Methods: Seven patients with old malunited femoral shaft fractures presented with disabling knee osteoarthritis between 1992 and 1999. Knee symptoms and function were graded at presentation. All underwent open femoral shaft osteotomy at the apex of the deformity, with locked intramedullary nail fixation. The patients were followed up regularly until osteotomy union and reviewed clinically and radiologically with particular emphasis on knee symptoms and function.

Results: There were six males and one female. The mean age at presentation was 55 years and mean time from the fracture was 28 years (range 13–35 years). The mean preoperative knee alignment angle was 5.60 varus (range O′12′). The mean time to osteotomy union was 28 months. The mean postoperative knee alignment angle was 20 valgus (range 50 valgus -50 varus). All patients reported significant improvement in knee symptoms and function. One osteotomy was followed by a serious vascular complication and the patient now has a stiff but pain free knee. One patient with very advanced osteoarthritis underwent an uncomplicated total knee replacement after osteotomy union and nail removal.

Conclusion: These patients presenting with severe disability at an age which is worryingly young for total knee arthroplasty present a difficult management problem. Five out seven patients had excellent symptomatic and functional improvement following the femoral shaft osteotomy. The possible need for knee replacement was delayed by at least 5 years and the eventual arthroplasty is likely to have been made less technically difficult and more functionally satisfactory as a result of the alignment correction.

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

Aims. This study aimed to uncover the hub long non-coding RNAs (lncRNAs) differentially expressed in osteoarthritis (OA) cartilage using an integrated analysis of the competing endogenous RNA (ceRNA) network and co-expression network. Methods. Expression profiles data of ten OA and ten normal tissues of human knee cartilage were obtained from the Gene Expression Omnibus (GEO) database (GSE114007). The differentially expressed messenger RNAs (DEmRNAs) and lncRNAs (DElncRNAs) were identified using the edgeR package. We integrated human microRNA (miRNA)-lncRNA/mRNA interactions with DElncRNA/DEmRNA expression profiles to construct a ceRNA network. Likewise, lncRNA and mRNA expression profiles were used to build a co-expression network with the WGCNA package. Potential hub lncRNAs were identified based on an integrated analysis of the ceRNA network and co-expression network. StarBase and Multi Experiment Matrix databases were used to verify the lncRNAs. Results. We detected 1,212 DEmRNAs and 49 DElncRNAs in OA and normal knee cartilage. A total of 75 dysregulated lncRNA-miRNA interactions and 711 dysregulated miRNA-mRNA interactions were obtained in the ceRNA network, including ten DElncRNAs, 69 miRNAs, and 72 DEmRNAs. Similarly, 1,330 dysregulated lncRNA-mRNA interactions were used to construct the co-expression network, which included ten lncRNAs and 407 mRNAs. We finally identified seven hub lncRNAs, named MIR210HG, HCP5, LINC00313, LINC00654, LINC00839, TBC1D3P1-DHX40P1, and ISM1-AS1. Subsequent enrichment analysis elucidated that these lncRNAs regulated extracellular matrix organization and enriched in osteoclast differentiation, the FoxO signalling pathway, and the tumour necrosis factor (TNF) signalling pathway in the development of OA. Conclusion. The integrated analysis of the ceRNA network and co-expression network identified seven hub lncRNAs associated with OA. These lncRNAs may regulate extracellular matrix changes and chondrocyte homeostasis in OA progress. Cite this article:Bone Joint Res. 2020;9(3):90–98

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

We report on the 5 year results of a randomized study comparing TKR performed using conventional instrumentation versus electromagnetic computer-assisted surgery. This study analysed patient reported outcome measures (PROMs) at 5 years utilising the American Knee Society Score (AKSS), Oxford Knee Score (OKS), the Short Form 36 score and range of motion (ROM). Of the 200 patients enrolled 125 completed 5 year follow up, 62 in the navigated group and 63 in the conventional group. There were 28 deceased patients, 29 withdrawals and 16 lost to follow-up. There was improvement in clinical function in most PROMs from 1-5 year follow up across both groups. OKS improved from a mean of 26.6 (12–55) to 35.1 (5–48). AKSS increased from 75.3 (0–100) to 78.4 (−10–100), SF36 from 58.9 (2.5–100) to 53.2 (0–100). ROM improved by an average 7 degrees from 110 degrees to 117 degrees (80–135). There was no statistically significant difference in PROMs between the groups at 5 years. Patients undergoing revision surgery were identified from the dataset and global PACS. There were no revisions within 5 years in the navigated group and 3 revisions in the conventional group, two for infection and one for mid-flexion instability, giving an all cause revision rate of 3.06% at 5 years for this group. There appears to be no significant advantage in clinical function for patients undergoing TKR for OA of the knee with electromagnetic navigation when compared to conventional techniques. There may be an advantage in reducing early revision rates using this technology

Several attempts have been made to treat medial compartment OA of the knee with mobile spacers. All have met with dismal failure. This presentation explores the history of attempts to treat OA in the younger knee with mobile spacers and explains why they were all doomed to fail. Sources of information for this presentation include the published peer reviewed literature, publically available documents, and an insiders view of some of the failed attempts to solve the problem of medial compartment OA with mobile spacers. All attempts to treat medial compartment OA of the knee with mobile spacers have failed. The unispacer has been a failure with a 60% revision rate at three years. The ABS intercushion had a 100% revision rate at one year and in many cases caused permanent damage to the host knees. The Salucartilage spacer was implanted in one patient only and failed within 48 hours. Mobile spacers do not work, are never likely to work, and are not indicated for the treatment of medial compartment osteoarthritis of the knee

Osteoarthritis (OA) is the fastest growing global health problem, with a total joint replacement being the only effective treatment for patients with end stage OA. Many groups are examining the use of bone marrow or adipose derived mesenchymal stem cells (MSCs) to repair cartilage, or modulate inflammation to promote healing, however, little efficacy in promoting cartilage repair, or reducing patient symptoms over temporary treatments such as micro-fracture has been observed. There is a growing body of literature demonstrating that MSCs derived from the synovial lining of the joint are superior in terms of chondrogenic differentiation and while improvements in clinical outcome measures have been observed with synovial MSCs, results from clinical studies are still highly variable. Based on our results, we believe this variability in clinical studies with MSCs results in part from the isolation, expansion and re-injection of distinct MSCs subtypes in normal vs. OA tissues, each with differing regenerating potential. However, it remains unknown if this heterogeneity is natural (e.g. multiple MSC subtypes present) or if MSCs are influenced by factors in vivo (disease state/stage). Therefore, in this study, we undertook an ‘omics’ screening approach on MSCs from normal and OA knee synovial tissue. Specifically, we characterized their global proteome and genomic expression patterns to determine if multiple MSC from normal and OA joints are distinct at the protein/gene expression level and/if so, what proteins/genes are differentially expressed between MSCs derived from normal and OA synovial tissue. Synovium tissue was collected from OA patients undergoing joint replacement and normal cadaveric knees. The in vitro adipogenic, chondrogenic and osteogenic differentiation potential of the MSCs was analyzed via qPCR and histology. Fully characterized MSC populations where then analyzed through an unbiased shotgun proteomics, and microarray analysis. Synovial MSCs isolated from both OA and normal knees demonstrated similar multipotent differentiation capacity. Likewise, both OA and normal MSCs display the typical MSCs cell surface marker profile in vitro (CD90+, CD44+, CD73+, CD105+). Using shotgun proteomics, 7720 unique peptides corresponding to 2183 proteins were identified and quantified between normal and OA MSCs. Of these 2183 proteins, 994 were equally expressed in normal and OA, MSCs, 324 were upregulated in OA MSCs (with 50 proteins exclusively expressed in OA MSCs), 630 proteins were upregulated in normal MSCs (with 16 proteins exclusively expressed in normal MSCs). Microarray analysis of normal and OA MSCs demonstrated a similar result in where, 967 genes were differentially expressed between normal and OA MSCs, with 423 genes upregulated in OA, and 544 genes upregulated in normal MSCs. In this project, we have demonstrated that although normal and OA synovial derived MSCs demonstrate similar multipotent differentiation potential and cell surface markers expression, these cells demonstrated significant differences at the molecular level (protein and gene expression). Further research is required to determine if these differences influence functional differences in vitro and/or in vivo and what drives this dramatic change in the regulatory pathways within normal vs. OA synovial MSCs

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

Introduction and aims: Osteoarthritis (OA) of the knee is a widespread problem, yet there is little known about the kinematics of the osteoarthritic knee, and nothing about the tibio-femoral contact pattern. This study aimed to describe the role of tibio-femoral interface events in articular surface wear and degenerative change. Method: Fourteen subjects with symptomatic OA in one knee, and no pain or injury in the contralateral knee were recruited. The tibio-femoral contact pattern was recorded for both knees, while performing a supine leg-press from 0 to 90 degrees flexion against a 150N load. Severity of osteoarthritis was measured by Kellgren Lawrence grade, bone mineral density (BMD) using Dual Energy X-ray Absorptiometry close to the subchondral bone, diagnostic MRI, and joint damage recorded at knee arthroplasty. Pain and disability was recorded using a WOMAC questionnaire. Results: Severity of OA in the knees ranged from grade two to four (mode=4) in the symptomatic knee, and from zero to three (mode=0) in the contralateral knee. Contact in the lateral compartment of the knee was more anterior on the tibial plateau than healthy knees (p≤ 0.01), and this was associated with severity of OA (p≤ 0.01). Contact in the medial compartment was also more anterior on the tibial plateau, and this was associated with severity of OA. Abnormality in tibio-femoral contact patterns was associated with disability reported by the WOMAC score (r= 0.54). There was no significant difference in BMD between the OA and contralateral knees. However, the BMD was correlated with pain and physical function of the WOMAC score, that is, as function decreased, bone density increased in the arthritic compartment (r = 0.49 to 0.63; p≤ 0.01). Conclusion: Severity of osteoarthritis was associated with loss of rollback normally coupled with flexion, especially in the lateral compartment. Consequently longitudinal rotation was lost. In severe osteoarthritis, ACL integrity did not affect the contact pattern. Kinematic abnormalities may explain loss of range of motion, and patterns of wear in osteoarthritic knees

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

The August 2012 Knee Roundup. 360. looks at: meniscal defects and a polyurethane scaffold; which is best between a single or double bundle; OA of the knee; how to resolve anterior knee pain; whether yoga can be bad for your menisci; metal ions in the serum; whether ACI is any good; the ACL; whether hyaluronic acid delays collagen degradation; and hyaluronan and patellar tendinopathy

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