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Aims Accumulated evidence indicates that local cell origins may ingrain differences in the phenotypic activity of human osteoblasts. We hypothesized that these differences may also exist in osteoblasts harvested from the same bone type at periarticular sites, including those adjacent to the fixation sites for total joint implant components. Methods Human osteoblasts were obtained from the acetabulum and femoral neck of seven patients undergoing total hip arthroplasty (THA) and from the femoral and tibial cuts of six patients undergoing total knee arthroplasty (TKA). Osteoblasts were extracted from the usually discarded bone via enzyme digestion, characterized by flow cytometry, and cultured to passage three before measurement of metabolic activity, collagen production, alkaline phosphatase (ALP) expression, and mineralization. Results Osteoblasts from the acetabulum showed lower proliferation (p = 0.034), cumulative collagen release (p < 0.001), and ALP expression (p = 0.009), and produced less mineral (p = 0.006) than those from the femoral neck. Osteoblasts from the tibia produced significantly less collagen (p = 0.021) and showed lower ALP expression than those from the distal femur. Conclusion We have demonstrated for the first time an anatomical regional variation in the biological behaviours of osteoblasts on either side of the hip and knee joint. The lower osteoblast proliferation, matrix production, and mineralization from the acetabulum compared to those from the proximal femur may be reflected in differences in bone formation and implant fixation at these sites. Cite this article: Bone Joint Res 2021;10(9):611–618.

ObjectivesTo determine how gene expression profiles in osteoarthritis joint tissues relate to patient phenotypes and whether molecular subtypes can be reproducibly captured by a molecular classification algorithm.MethodsWe analysed RNA sequencing data from cartilage and synovium in 113 osteoarthritis patients, applying unsupervised clustering and Multi-Omics Factor Analysis to characterise transcriptional profiles. We tested the association of the molecularly defined patient subgroups with clinical characteristics from electronic health records.ResultsWe detected two patient subgroups in low-grade cartilage (showing no/minimal degeneration, cartilage normal/softening only), with differences associated with inflammation, extracellular matrix-related and cell adhesion pathways. The high-inflammation subgroup was associated with female sex (OR 4.12, p=0.0024) and prescription of proton pump inhibitors (OR 4.21, p=0.0040). We identified two independent patient subgroupings in osteoarthritis synovium: one related to inflammation and the other to extracellular matrix and cell adhesion processes. A seven-gene classifier including MMP13, APOD, MMP2, MMP1, CYTL1, IL6 and C15orf48 recapitulated the main axis of molecular heterogeneity in low-grade knee osteoarthritis cartilage (correlation ρ=−0.88, p−10) and was reproducible in an independent patient cohort (ρ=−0.85, p−10).ConclusionsThese data support the reproducible stratification of osteoarthritis patients by molecular subtype and the exploration of new avenues for tailored treatments.

Aims To investigate factors that contribute to patient decisions regarding attendance for arthroplasty during the COVID-19 pandemic. Methods A postal questionnaire was distributed to patients on the waiting list for hip or knee arthroplasty in a single tertiary centre within the UK. Patient factors that may have influenced the decision to attend for arthroplasty, global quality of life (QoL) (EuroQol five-dimension three-level (EQ-5D-3L)), and joint-specific QoL (Oxford Hip or Knee Score) were assessed. Patients were asked at which ‘COVID-alert’ level they would be willing to attend an NHS and a “COVID-light” hospital for arthroplasty. Independent predictors were assessed using multivariate logistic regression. Results Of 540 distributed questionnaires, 400 (74.1%; 236 awaiting hip arthroplasty, 164 awaiting knee arthroplasty) complete responses were received and included. Less than half (48.2%) were willing to attend for hip or knee arthroplasty while a UK COVID-19 epidemic was in circulation (COVID-alert levels 3 to 5). Patients with worse joint-specific QoL had a preference to proceed with surgery at COVID-alert levels 3 to 5 compared to levels 1 and 2 (hip arthroplasty odds ratio (OR) 1.54 (95% confidence interval (CI) 1.45 to 1.63); knee arthroplasty OR 1.16 (1.07 to 1.26)). The odds of patients with worse joint-specific QoL being willing to attend for surgery at COVID-alert levels 3 to 5 increased further if surgery in a private, “COVID-light” hospital was available (hip arthroplasty OR 3.50 (95% CI 3.26 to 3.71); knee arthroplasty OR 1.41 (95% CI 1.29 to 1.53). Conclusion Patient decisions surrounding elective surgery have been influenced by the global COVID-19 pandemic, highlighting the importance of patient involvement in ensuring optimized provision of elective surgery during these challenging times. Cite this article: Bone Jt Open 2021;2(4):261–270.

Background: Traditional quantitative analysis of cartilage with MRI averages measurements (eg, thickness) across regions-of-interest (ROIs) which may reduce responsiveness. Purpose: To validate and describe clinical application of a semiautomated surface-based method for analyzing cartilage relaxation times (“composition”) and morphology on MRI, 3D cartilage surface mapping (3D-CaSM). Study Type: Validation study in cadaveric knees and prospective observational (cohort) study in human participants. Population: Four cadaveric knees and 14 participants aged 40–60 with mild–moderate knee osteoarthritis (OA) and 6 age-matched healthy volunteers, imaged at baseline, 1, and 6 months. Field Strength/Sequence: 3D spoiled gradient echo, T 1rho/T 2 magnetization-prepared 3D fast spin echo for mapping of T 1rho/T 2 relaxation times and delayed gadolinium enhanced MRI of cartilage (dGEMRIC) using variable flip angle T 1 relaxation time mapping at 3T. Assessment: 3D-CaSM was validated against high-resolution peripheral quantitative computed tomography (HRpQCT) in cadaveric knees, with comparison to expert manual segmentation. The clinical study assessed test–retest repeatability and sensitivity to change over 6 months for cartilage thickness and relaxation times. Statistical Tests: Bland–Altman analysis was performed for the validation study and evaluation of test–retest repeatability. Six-month changes were assessed via calculation of the percentage of each cartilage surface affected by areas of significant change (%SC), defined using thresholds based on area and smallest detectable difference (SDD). Results: Bias and precision (0.06 ± 0.25 mm) of 3D-CaSM against reference HRpQCT data were comparable to expert manual segmentation (−0.13 ± 0.26 mm). 3D-CaSM demonstrated significant (>SDD) 6-month changes in cartilage thickness and relaxation times in both OA participants and healthy controls. The parameter demonstrating the greatest 6-month change was T 2 relaxation time (OA median %SC [IQR] = 8.8% [5.5 to 12.6]). Data Conclusion: This study demonstrates the construct validity and potential clinical utility of 3D-CaSM, which may offer advantages to conventional ROI-based methods. Level of Evidence: 2. Technical Efficacy Stage: 2. J. Magn. Reson. Imaging 2020;52:1139–1151.

Fractures of the tibia are frequently treated with an intra-medullary nail. This can be inserted through either a supra-patella or infra-patella surgical incision. Concerns over potential damage to the cartilage of the knee with supra-patella insertion has impacted upon its adoption despite benefits in terms of easier nail placement and potentially reduced blood loss and pain.This randomised pilot study will use patient reported outcome measures (PROMS) and novel MRI sequences designed to assess damage to the structure of cartilage to compare these two methods of tibial intra-medullary nailing.Twenty individuals with tibial shaft fractures will be randomised to either method of nail insertion (ten individuals in each arm). MRI scans and PROMS will be used to assess cartilage damage and general function up to 6 months post operatively.The results of the study will be used to inform a potential multi-centre study.

Objectives Evaluate test-retest repeatability, ability to discriminate between osteoarthritic and healthy participants, and sensitivity to change over 6 months, of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) biomarkers in knee OA. Methods Fourteen individuals aged 40–60 with mild-moderate knee OA and 6 age-matched healthy volunteers (HV) underwent DCE-MRI at 3 T at baseline, 1 month and 6 months. Voxelwise pharmacokinetic modelling of dynamic data was used to calculate DCE-MRI biomarkers including Ktrans and IAUC60. Median DCE-MRI biomarker values were extracted for each participant at each study visit. Synovial segmentation was performed using both manual and semiautomatic methods with calculation of an additional biomarker, the volume of enhancing pannus (VEP). Test-retest repeatability was assessed using intraclass correlation coefficients (ICC). Smallest detectable differences (SDDs) were calculated from test-retest data. Discrimination between OA and HV was assessed via calculation of between-group standardised mean differences (SMD). Responsiveness was assessed via the number of OA participants with changes greater than the SDD at 6 months. Results Ktrans demonstrated the best test-retest repeatability (Ktrans/IAUC60/VEP ICCs 0.90/0.84/0.40, SDDs as % of OA mean 33/71/76%), discrimination between OA and HV (SMDs 0.94/0.54/0.50) and responsiveness (5/1/1 out of 12 OA participants with 6-month change > SDD) when compared to IAUC60 and VEP. Biomarkers derived from semiautomatic segmentation outperformed those derived from manual segmentation across all domains. Conclusions Ktrans demonstrated the best repeatability, discrimination and sensitivity to change suggesting that it is the optimal DCE-MRI biomarker for use in experimental medicine studies. Key Points • Dynamic contrast-enhanced MRI (DCE-MRI) provides quantitative measures of synovitis in knee osteoarthritis which may permit early assessment of efficacy in experimental medicine studies. • This prospective observational study compared DCE-MRI biomarkers across domains relevant to experimental medicine: test-retest repeatability, discriminative validity and sensitivity to change. • The DCE-MRI biomarker Ktransdemonstrated the best performance across all three domains, suggesting that it is the optimal biomarker for use in future interventional studies.

Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis., Understanding the molecular effects of disease variants in relevant tissues is essential to understanding and treating disease. Here, the authors discover expression and protein quantitative trait loci in cartilage and synovium from 115 osteoarthritis patients to pinpoint genes of action and potential drug treatments.

Cartilage loss leads to osteoarthritis, the most common cause of disability for which there is no cure. Cartilage regeneration, therefore, is a priority in medicine. We report that agrin is a potent chondrogenic factor and that a single intraarticular administration of agrin induced long-lasting regeneration of critical-size osteochondral defects in mice, with restoration of tissue architecture and bone-cartilage interface. Agrin attracted joint resident progenitor cells to the site of injury and, through simultaneous activation of CREB and suppression of canonical WNT signaling downstream of β-catenin, induced expression of the chondrogenic stem cell marker GDF5 and differentiation into stable articular chondrocytes, forming stable articular cartilage. In sheep, an agrin-containing collagen gel resulted in long-lasting regeneration of bone and cartilage, which promoted increased ambulatory activity. Our findings support the therapeutic use of agrin for joint surface regeneration.

The treatment of chondral defects using microdrilling often results in a mechanically weak fibrocartilagenous repair, rather than a more robust hyaline cartilage repair. Many different microfracture/microdrilling augmentation techniques have been described, including the use of cellular products to enhance healing. Autologous peripheral blood progenitor cells can be obtained via apheresis after administration of granulocyte colony stimulating factor (G-CSF) and have been used successfully augment microdrilling in clinical patients. The objective of this study was to use apheresis derived mononuclear blood cells to augment microdrilling treatment of a cartilage defect in an ovine model in order to determine the effect on healing. Forty adult female sheep were used in this study and were divided into a control group (microdrilling alone) and a treatment group (microdrilling, hyaluronic acid and apheretic product). Outcome measurements included weight bearing on the operated limb, macroscopic scoring of the joint, histology and immunohistochemistry. In addition, MRI was used to attempt to identify SPION labelled cells from the apheretic product in the operated limbs. The results showed a significant increase in healing as measured by the modified O'Driscoll sore in the treated group. No evidence of homing of SPION labelled cells to the defect was found and no correlation was found between the response to G-CSF administration or concentration of CD34+ve and outcome. A correlation was found between healing and the concentration of white blood cells and peripheral blood mononuclear cell numbers in the apheretic product. This article is protected by copyright. All rights reserved.

Objectives To identify molecular differences between chondrocytes from osteophytic and articular cartilage tissue from OA patients. Methods We investigated genes and pathways by combining genome-wide DNA methylation, RNA sequencing and quantitative proteomics in isolated primary chondrocytes from the cartilaginous layer of osteophytes and matched areas of low- and high-grade articular cartilage across nine patients with OA undergoing hip replacement surgery. Results Chondrocytes from osteophytic cartilage showed widespread differences to low-grade articular cartilage chondrocytes. These differences were similar to, but more pronounced than, differences between chondrocytes from osteophytic and high-grade articular cartilage, and more pronounced than differences between high- and low-grade articular cartilage. We identified 56 genes with significant differences between osteophytic chondrocytes and low-grade articular cartilage chondrocytes on all three omics levels. Several of these genes have known roles in OA, including ALDH1A2 and cartilage oligomeric matrix protein, which have functional genetic variants associated with OA from genome-wide association studies. An integrative gene ontology enrichment analysis showed that differences between osteophytic and low-grade articular cartilage chondrocytes are associated with extracellular matrix organization, skeletal system development, platelet aggregation and regulation of ERK1 and ERK2 cascade. Conclusion We present a first comprehensive view of the molecular landscape of chondrocytes from osteophytic cartilage as compared with articular cartilage chondrocytes from the same joints in OA. We found robust changes at genes relevant to chondrocyte function, providing insight into biological processes involved in osteophyte development and thus OA progression.

Introduction The weekend effect is a perceived difference in outcome between medical care provided at the weekend when compared to that of a weekday. Clearly multifactorial, this effect remains incompletely understood and variable in different clinical contexts. In this study we analyse factors relevant to the weekend effect in elective lower-limb joint replacement at a large NHS multispecialty academic healthcare centre. Materials and Methods We reviewed the electronic medical records of 352 consecutive patients who received an elective primary hip or knee arthroplasty. Patient, clinical and time-related variables were extracted from the records. The data were anonymised, then processed using a combination of uni- and multivariate statistics. Results There is a significant association between the selected weekend effect outcome measure (postoperative length of stay) and patient age, American Society of Anesthesiologists classification, time to first postoperative physiotherapy and time to postoperative radiography but not day of the week of operation. Discussion We were not able to demonstrate a weekend effect in elective lower-limb joint replacement at our institution nor identify a factor that would require additional weekend clinical medical staffing. Rather, resource priorities would seem to include measures to optimise at-risk patients preoperatively and measures to reduce time to physiotherapy and radiography postoperatively. Conclusions Our findings imply that postoperative length of stay could be minimised by strategies relating to patient selection and access to postoperative services. We have also identified a powerful statistical methodology that could be applied to other service evaluations in different clinical contexts.

Osteoarthritis is a serious joint disease that causes pain and functional disability for a quarter of a billion people worldwide1, with no disease-stratifying tools nor modifying therapy. Here, we use primary chondrocytes, synoviocytes and peripheral blood from patients with osteoarthritis to construct a molecular quantitative trait locus map of gene expression and protein abundance in disease. By integrating data across omics levels, we identify likely effector genes for osteoarthritis-associated genetic signals. We detect stark molecular differences between macroscopically intact (low-grade) and highly degenerated (high-grade) cartilage, reflecting activation of the extracellular matrix-receptor interaction pathway. Using unsupervised consensus clustering on transcriptome-wide sequencing, we identify molecularly-defined patient subgroups that correlate with clinical characteristics. Between-cluster differences are driven by inflammation, presenting the opportunity to stratify patients on the basis of their molecular profile for tailored intervention. We construct and validate a 7-gene classifier that reproducibly distinguishes between these disease subtypes. Finally, we identify potentially actionable compounds for disease modification and drug repositioning. Our findings contribute to both patient stratification and therapy development in this globally important area of unmet need.

Tissue engineering is a promising alternative that may facilitate bony regeneration in small defects in compromised host tissue as well as large mandibular defects. This scoping systematic review was therefore designed to assess in vivo research on its use in the reconstruction of mandibular defects in animal models. A total of 4524 articles were initially retrieved using the search algorithm. After screening of the titles and abstracts, 269 full texts were retrieved, and a total of 72 studies included. Just two of the included studies employed osteonecrosis as the model of mandibular injury. All the rest involved the creation of a critical defect. Calcium phosphates, especially tricalcium phosphate and hydroxyapatite, were the scaffolds most widely used. All the studies that used a scaffold reported increased formation of bone when compared with negative controls. When combined with scaffolds, mesenchymal stem cells (MSC) increased the formation of new bone and improved healing. Various growth factors have been studied for their potential use in the regeneration of the maxillofacial complex. Bone morphogenic proteins (BMP) were the most popular, and all subtypes promoted significant formation of bone compared with controls. Whilst the studies published to date suggest a promising future, our review has shown that several shortfalls must be addressed before the findings can be translated into clinical practice. A greater understanding of the underlying cellular and molecular mechanisms is required to identify the optimal combination of components that are needed for predictable and feasible reconstruction or regeneration of mandibular bone. In particular, a greater understanding of the biological aspects of the regenerative triad is needed before we can to work towards widespread translation into clinical practice.

Background:Cartilage defects in the joints are reported in 61% of all arthroscopies1&2. The size of the cartilage repair market is estimated to be $2.195 million by 20253. Cartilage defects can evolve into osteoarthritis, in which abnormal load results in cartilage breakdown, joint pain and reduced mobility. Osteoarthritis is the leading cause of permanent disability and absenteeism and affects up to 1/3 of the people over 60yrs. In western countries osteoarthritis costs 1.5-2% of the GDP4. Joint replacement with a prosthesis restores some degree of independence but in up to 20% of patients it does not meet expectations 5 and has a limited life span. There is no pharmacological intervention that arrests or reverts the course of osteoarthritis, despite the desperate need.We previously published that agrin plays an important role in cartilage homeostasis6. The addition of agrin to chondrocytes in vivo resulted in enhanced cartilage formation, suggesting a potential role for agrin in cartilage repair.Objectives:Investigate the potential of agrin for use in cartilage repair.Methods:Critical size osteochondral defects were generated in mice and sheep and injected intraarticularly with type I collagen gel containing agrin or vehicle. Animals were monitored for 8 weeks or 6 months respectively. MicroCT, histological analysis, qPCR, linage tracking, reporter assays, chondrogenesis assay, immunohistochemistry were performed.Results:A single intraarticular administration of agrin induced regeneration of critical-size osteochondral defects in mice, restoring the tissue architecture and bone-cartilage interface. Agrin stem cells to the site of injury and, through simultaneous activation of CREB and suppression of canonical WNT signalling, induced GDF5 expression and differentiation into stable articular chondrocytes, forming stable articular cartilage. In sheep, agrin treatment resulted in regeneration of bone and cartilage, which promoted increased ambulatory activity.Conclusion:Agrin orchestrates repair morphogenesis at the joint surface by modulating multiple signalling pathways, supporting the therapeutic use of agrin for joint surface regeneration.References:[1]Curl, W. W. et al. Cartilage injuries: a review of 31,516 knee arthroscopies. Arthrosc. J. Arthrosc. Relat. Surg. Off. Publ. Arthrosc. Assoc. N. Am. Int. Arthrosc. Assoc. 13, 456–460 (1997).[2]Hjelle, K., Solheim, E., Strand, T., Muri, R. & Brittberg, M. Articular cartilage defects in 1,000 knee arthroscopies. Arthrosc. J. Arthrosc. Relat. Surg. Off. Publ. Arthrosc. Assoc. N. Am. Int. Arthrosc. Assoc. 18, 730–734 (2002).[3]Cartilage Repair Market Size, Share, Industry Analysis 2018-2025 | AMR. Allied Market Research https://www.alliedmarketresearch.com/cartilage-repair-market.[4]Hiligsmann, M. et al. Health economics in the field of osteoarthritis: an expert’s consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Semin. Arthritis Rheum. 43, 303–313 (2013).[5]Dieppe, P., Lim, K. & Lohmander, S. Who should have knee joint replacement surgery for osteoarthritis? Int. J. Rheum. Dis. 14, 175–180 (2011).[6]Eldridge, S., et al. Agrin mediates chondrocyte homeostasis and requires both LRP4 and α-dystroglycan to enhance cartilage formation in vitro and in vivo. Annals of the rheumatic diseases 75 (6), 1228-1235 (2016).Acknowledgements:We thank the technical staff in the ARM Lab and Staff at the University of Aberdeen’s Animal Facility and Microscopy and Histology Facility for support. Funding: We gratefully acknowledge funding support of this work by the MRC (MR/L022893/1, MR/N010973/1,and MR/P026362/1), Versus Arthritis (19667, 21515, 20886, and 21621), Rosetrees Trust (A1205), the Medical College of St Bartholomew’s Hospital Trust, and the William Harvey Research Foundation.Disclosure of Interests:Suzanne Eldridge: None declared, Aida Barawi: None declared, Hui Wang: None declared, Anke Roelofs: None declared, Magdalena Kaneva: None declared, Zeyu Guan: None declared, Helen Lydon: None declared, Bethan Thomas: None declared, Anne-Sophie Thorup: None declared, Beatriz F Fernandez: None declared, Sara Caxaria: None declared, Danielle Strachan: None declared, Ahmed Ali: None declared, Kanatheepan Shanmuganathan: None declared, Costantino Pitzalis: None declared, James Whiteford: None declared, Fran Henson: None declared, Andrew McCaskie: None declared, Cosimo De Bari: None declared, Francesco Dell’Accio Consultant of: F.D. has received consultancy fees from Samumed and UCB.

Objectives To assess whether initial or 12–18-month change in magnetic resonance imaging (MRI) subchondral bone texture is predictive of radiographic knee osteoarthritis (OA) progression over 36 months. Methods This was a nested case-control study including 122 knees/122 participants in the Osteoarthritis Initiative (OAI) Bone Ancillary Study, who underwent MRI optimised for subchondral bone assessment at either the 30- or 36-month and 48-month OAI visits. Case knees (n = 61) had radiographic OA progression between the 36- and 72-month OAI visits, defined as ≥ 0.7 mm minimum medial tibiofemoral radiographic joint space (minJSW) loss. Control knees (n = 61) without radiographic OA progression were matched (1:1) to cases for age, sex, body mass index and initial medial minJSW. Texture analysis was performed on the medial femoral and tibial subchondral bone. We assessed the association of texture features with radiographic progression by creating a composite texture score using penalised logistic regression and calculating odds ratios. We evaluated the predictive performance of texture features for predicting radiographic progression using c-statistics. Results Initial (odds ratio [95% confidence interval] = 2.13 [1.41–3.40]) and 12– 18-month change (3.76 [2.04–7.82]) texture scores were significantly associated with radiographic OA progression. Combinations of texture features were significant predictors of radiographic progression using initial (c-statistic [95% confidence interval] = 0.65 [0.64–0.65], p = 0.003) and 12–18-month change (0.68 [0.68-0.68], p < 0.001) data. Conclusions Initial and 12–18-month changes in MRI subchondral bone texture score were significantly associated with radiographic progression at 36 months, with better predictive performance for 12–18-month change in texture. These results suggest that texture analysis may be a useful biomarker of subchondral bone in OA. Key Points • Subchondral bone MRI texture analysis is a promising knee osteoarthritis imaging biomarker. • In this study, subchondral bone texture was associated with knee osteoarthritis progression. • This demonstrates predictive and concurrent validity of MRI subchondral bone texture analysis. • This method may be useful in clinical trials with interventions targeting bone. Electronic supplementary material The online version of this article (10.1007/s00330-018-5444-9) contains supplementary material, which is available to authorized users.

A novel apatite-wollastonite/poly(lactic acid) (AW/PLA) composite structure, which matches cortical and cancellous bone properties has been produced and evaluated in vitro and in vivo. The composites structure has been produced using an innovative combination of 3D printed polymer and ceramic macrostructures, thermally bonded to create a hybrid composite structure. In vitro cell assays demonstrated that the AW structure alone, PLA structure alone, and AW/PLA composite were all biocompatible, with the AW structure supporting the proliferation and osteogenic differentiation of rat bone marrow stromal cells. Within a rat calvarial defect model the AW material showed excellent osseointegration with the formation of new bone, and vascularisation of the porous AW structure, both when the AW was implanted alone and when it was part of the AW/PLA composite structure. However, the AW/PLA structure showed the largest amount of the newly formed bone in vivo, an effect which is considered to be a result of the presence of the osteoinductive AW structure stimulating bone growth in the larger pores of the adjacent PLA structure. The layered AW/PLA structure showed no signs of delamination in any of the in vitro or in vivo studies, a result which is attributed to good initial bonding between polymer and ceramic, slow resorption rates of the two materials, and excellent osseointegration. It is concluded that macro-scale composites offer an alternative route to the fabrication of bioactive bone implants which can provide a match to both cortical and cancellous bone properties over millimetre length scales.

Charcot neuroarthropathy is a rare but serious complication of diabetes, causing progressive destruction of the bones and joints of the foot leading to deformity, altered biomechanics and an increased risk of ulceration. Management is complicated by a lack of consensus on diagnostic criteria and an incomplete understanding of the pathogenesis. In this review, we consider recent insights into the development of Charcot neuroarthropathy. It is likely to be dependent on several interrelated factors which may include a genetic pre-disposition in combination with diabetic neuropathy. This leads to decreased neuropeptides (nitric oxide and calcitonin gene-related peptide), which may affect the normal coupling of bone formation and resorption, and increased levels of Receptor activator of nuclear factor kappa-B ligand, potentiating osteoclastogenesis. Repetitive unrecognized trauma due to neuropathy increases levels of pro-inflammatory cytokines (interleukin-1β, interleukin-6, tumour necrosis factor α) which could also contribute to increased bone resorption, in combination with a pre-inflammatory state, with increased autoimmune reactivity and a profile of monocytes primed to transform into osteoclasts - cluster of differentiation 14 (CD14). Increased blood glucose and loss of circulating Receptor for Advanced Glycation End-Products (AGLEPs), leading to increased non-enzymatic glycation of collagen and accumulation of AGLEPs in the tissues of the foot, may also contribute to the pathological process. An understanding of the relative contributions of each of these mechanisms and a final common pathway for the development of Charcot neuroarthropathy are still lacking. Cite this article: S. E. Johnson-Lynn, A. W. McCaskie, A. P. Coll, A. H. N. Robinson. Neuroarthropathy in diabetes: pathogenesis of Charcot arthropathy. Bone Joint Res 2018;7:373–378. DOI: 10.1302/2046-3758.75.BJR-2017-0334.R1.

Background Osteoarthritis(OA)in the knee exhibits signs of synovial activation in early phase of disease(.1 DCE-MRI provides quantitative measurement of vascular disruption associated with synovitis(2,3and has been shown to be sensitive to early treatment-induced changes in small group sizes in multicentre trials(.4 Objectives 1. Determine the reproducibility of DCE-MRI parameters in the knee. 2. Compare DCE-MRI parameters between participants with mild/moderate OA and aged matched controls. 3. Enable effect and sample size calculations for further studies. Methods 9 knee OA patients and 4 controls underwent two MRI scans with a month separation. All patients had diagnosis of knee OA as per ACR criteria, with medial compartment predominant disease and Kellgren-Lawrence grade 2/3 on radiographs. 3 pre-contrast injection series were obtained with flip angles 2o,6o and 14ofor T1 calculation.35 consecutive phases formed the DCE-MRI series(temporal resolution:14 s). Contrast agent(CA)(Dotarem(0.4 mL/kg))was administrated on the 6th phase at the rate 3 mL/s followed by 50 mL saline. All Images were registered together. Here 2 DCE paramaters are reported:Ktrans(min-1), volume transfer constant for CA between blood plasma and extravascular extracellular space; estimated using the extended Tofts model(5 with population arterial function(;6 and IAUC60(mM.s), initial area under CA concentration curve over 60 s post-arrival. Manual segmentation was performed by radiologist. Results Test-retest coefficient of variation(CoV) was lower in controls. Ktranshad CoVs of 26/16% in OA patients/controls. An effect size of 30% reduction in Ktrans(,4 indicates a treatment effect would be observed in a group of 11 patients with 90% power. DCE parameters were generally higher in OA patients than in controls. 4 out of 9 patients (All with KL score 3)demonstrated parameter values outside the healthy volunteer range at p Conclusions Higher Ktransand IAUC60in patients indicates the potential of revealing microvascular function differences. The fact that this is not observed in all patients could suggest phenotypical variation. High CoV values in patient relative to healthy may be explained in part by fluctuation in disease status. Manual delineation also contributes to this variation. DCE-MRI measures of vascular disruption associated with synovitis in knee OA are practical and feasible for imaging trials. These measures offer greater insight and sensitivity into the inflammatory component of OA that is not captured using other radiological methods. References [1] Roemer, et al. Osteoarthr Cartil.2010;1269–74. [2] Wenham, et al. Osteoarthr Cartil.2014; 1614–18. [3] Gait, et al. Osteoarthr. Cartil2016;1392–8. [4] Waterton, et al. Eu. Rad2017;3662–8. [5] Tofts, et al. JMRI.1999;223–32. [6] Parker, et al MRM2006:993–1000. Acknowledgements National Institute for Health Research Cambridge Biomedical Research Centre. Funding provided by GlaxoSmithKline. Disclosure of Interest None declared

OBJECTIVE: To assess reliability and discriminative validity of cartilage compositional magnetic resonance imaging (MRI) in knee osteoarthritis (OA). DESIGN: The study was carried out per PRISMA recommendations. We searched MEDLINE and EMBASE (1974 - present) for eligible studies. We performed qualitative synthesis of reliability data. Where data from at least two discrimination studies were available, we estimated pooled standardized mean difference (SMD) between subjects with and without OA. Discrimination analyses compared controls and subjects with mild OA (Kellgren-Lawrence (KL) grade 1-2), severe OA (KL grade 3-4) and OA not otherwise specified (NOS) where not possible to stratify. We assessed quality of the evidence using Quality Appraisal of Diagnostic Reliability (QAREL) and Quality Assessment of Diagnostic Accuracy (QUADAS-2) tools. RESULTS: Fifty-eight studies were included in the reliability analysis and 26 studies were included in the discrimination analysis, with data from a total of 2,007 knees. Intra-observer, inter-observer and test-retest reliability of compositional techniques were excellent with most intraclass correlation coefficients >0.8 and coefficients of variation

Osteoarthritis (OA) is a common disease characterized by cartilage degeneration and joint remodeling. The underlying molecular changes underpinning disease progression are incompletely understood. We investigated genes and pathways that mark OA progression in isolated primary chondrocytes taken from paired intact versus degraded articular cartilage samples across 38 patients undergoing joint replacement surgery (discovery cohort: 12 knee OA, replication cohorts: 17 knee OA, 9 hip OA patients). We combined genome-wide DNA methylation, RNA sequencing, and quantitative proteomics data. We identified 49 genes differentially regulated between intact and degraded cartilage in at least two –omics levels, 16 of which have not previously been implicated in OA progression. Integrated pathway analysis implicated the involvement of extracellular matrix degradation, collagen catabolism and angiogenesis in disease progression. Using independent replication datasets, we showed that the direction of change is consistent for over 90% of differentially expressed genes and differentially methylated CpG probes. AQP1, COL1A1 and CLEC3B were significantly differentially regulated across all three –omics levels, confirming their differential expression in human disease. Through integration of genome-wide methylation, gene and protein expression data in human primary chondrocytes, we identified consistent molecular players in OA progression that replicated across independent datasets and that have translational potential.

Osteoarthritis is a common complex disease with huge public health burden. Here we perform a genome-wide association study for osteoarthritis using data across 16.5 million variants from the UK Biobank resource. Following replication and meta-analysis in up to 30,727 cases and 297,191 controls, we report 9 new osteoarthritis loci, in all of which the most likely causal variant is non-coding. For three loci, we detect association with biologically-relevant radiographic endophenotypes, and in five signals we identify genes that are differentially expressed in degraded compared to intact articular cartilage from osteoarthritis patients. We establish causal effects for higher body mass index, but not for triglyceride levels or type 2 diabetes liability, on osteoarthritis.

Osteoarthritis is a common complex disease imposing a large public-health burden. Here, we performed a genome-wide association study for osteoarthritis, using data across 16.5 million variants from the UK Biobank resource. After performing replication and meta-analysis in up to 30,727 cases and 297,191 controls, we identified nine new osteoarthritis loci, in all of which the most likely causal variant was noncoding. For three loci, we detected association with biologically relevant radiographic endophenotypes, and in five signals we identified genes that were differentially expressed in degraded compared with intact articular cartilage from patients with osteoarthritis. We established causal effects on osteoarthritis for higher body mass index but not for triglyceride levels or genetic predisposition to type 2 diabetes.

This article reports on the use of the binder jetting three-dimensional printing process combined with sintering to process bioceramic materials to form micro- and macroporous three-dimensional structures. Three different glass-ceramic formulations, apatite–wollastonite and two silicate-based glasses, have been processed using this route to create porous structures which have Young’s modulus equivalent to cortical bone and average bending strengths in the range 24–36 MPa. It is demonstrated that a range of macroporous geometries can be created with accuracies of ±0.25 mm over length scales up to 40 mm. Hot-stage microscopy is a valuable tool in the definition of processing parameters for the sintering step of the process. Overall, it is concluded that binder jetting followed by sintering offers a versatile process for the manufacture of load-bearing bioceramic components for bone replacement applications.

PURPOSE The utility of magnetic resonance imaging (MRI) quantitative imaging biomarkers (QIBs) of cartilage in experimental medicine studies of potential disease modifying osteoarthritis treatments (DMOATs) is uncertain due to the small sample sizes and short follow-up involved. To be relevant to such studies, candidate QIBs must demonstrate acceptable repeatability, discriminative ability and responsiveness. The purpose of this study was to evaluate test-retest repeatability and discriminative ability of 4 cartilage QIBs at the knee (thickness, T1rho, T2 and delayed gadolinium enhanced MRI of cartilage [dGEMRIC]) to assess their utility in experimental medicine studies. METHODS We imaged 9 participants with mild-moderate knee osteoarthritis (OA), characterised by radiographs with medial tibiofemoral predominant disease and Kellgren-Lawrence grades 2-3, and 4 healthy volunteers (HVs) matched for age, sex and body mass index. Participants were imaged at baseline and 1 month. MR studies were performed on a 3T system (MR 750, GE Healthcare) and were split into 2 sessions. The first MR session included a 3-dimensional spoiled gradient echo (3D SPGR) sequence and T1rho and T2 mapping sequences. At the end of this session, we administered an intravenous gadolinium based contrast agent (Dotarem, Guerbet LLC) at double dose (0.2 mmol/kg). Participants then performed 10 minutes of exercise on a stationary cycle to facilitate contrast penetration into the joint for dGEMRIC. The second MR session began 90 minutes following injection of contrast agent and consisted of T1 mapping using a variable flip angle technique. MR pulse sequence details are provided in table 1. We performed surface based analysis of cartilage parameters using Stradwin software (http://mi.eng.cam.ac.uk/~rwp/stradwin). In brief, this consists of semi-automated thickness measurement on 3D SPGR images, with generation of accurate inner and outer cartilage surfaces. Following rigid registration of the compositional (T1rho, T2, dGEMRIC) data to the 3D SPGR images, the same surfaces were used to sample the compositional data. This analysis pipeline allows each parameter to be measured at ~5,000 surface vertices per participant. We assessed overall (pooled OA and HV data) test-retest repeatability by calculating the root-mean-square coefficient of variation (RMS-CV) and the smallest detectable change (SDC) for each parameter. We assessed overall discriminative validity by estimating effect sizes for the difference in the mean value of each parameter in OA participants and HVs. We also mapped the test-retest errors and mean difference in each parameter between groups onto a representative surface for each cartilage region. RESULTS Participant characteristics are provided in table 2. RMS-CVs, SDCs and effect size estimates are provided in table 3. Overall test-retest RMS-CV values ranged from 2.5% (T1rho) to 10.3% (dGEMRIC). The largest overall effect size was demonstrated for dGEMRIC (-1.3, 90% confidence interval [CI] -2.3 to -0.2), followed by thickness (-0.67, 90% CI -1.5 to 0.3), T1rho and T2 (both 0.61, 90% CI -0.4 to 1.5). Mapping of test-retest errors and between-group differences to a representative surface revealed substantial spatial heterogeneity in these metrics for all parameters (figure 1). This suggests that surface based approaches may offer improved sensitivity over traditional region of interest based measurements. CONCLUSION This study demonstrates that cartilage QIBs may be useful in experimental medicine studies of knee osteoarthritis. Statistical approaches reflecting the spatial heterogeneity of changes in cartilage should be used to provide an indication of where significant results are located, not just whether an average value is significantly different. Future work will evaluate responsiveness of these cartilage QIBs.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. We performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. We accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis). Novel genetic loci for hip OA were found in this meta-analysis of GWAS. info:eu-repo/grantAgreement/EC/FP7/200800 info:eu-repo/grantAgreement/EC/FP7/286213

Poor knee extension function after total knee arthroplasty (TKA) is associated with factors including articular geometry and alignment. Femoral trochlear geometry has evolved from symmetrical to become more prominent proximal–laterally, with the groove aligned proximal–lateral to distal–medial. This study in vitro tested the hypothesis that a modern asymmetrical prosthesis would restore patellar tracking and stability to more natural behaviour than an older symmetrical prosthesis. Six knees had their patellar tracking measured optically during active knee extension. Medial–lateral force versus displacement stability was measured at fixed angles of knee flexion. The measurements were repeated after inserting each of the symmetrical and asymmetrical TKAs. Significant differences of patellar lateral displacement stability, compared to normal, were not found at any angle of knee flexion. The patella tracked medial–laterally within 2.5 mm of the natural path with both TKAs. However, for both TKAs near knee extension, the patella was tilted laterally by approximately 6° and was also flexed approximately 8° more than in the natural knee. The hypothesis was not supported: The more anatomical component design did not provide more anatomical patellar kinematics and stability.

Stem cells are a key component of regenerative medicine strategies. Particular areas of musculoskeletal application include cartilage and bone regeneration in arthritis and trauma. There are several types of stem cell and this article will focus on the adult derived cells. The review includes current issues and future developments.

Osteoarthritis (OA) is a common complex disease with high public health burden and no curative therapy. High bone mineral density (BMD) is associated with an increased risk of developing OA, suggesting a shared underlying biology. Here, we performed the first systematic overlap analysis of OA and BMD on a genome wide scale. We used summary statistics from the GEFOS consortium for lumbar spine (n = 31,800) and femoral neck (n = 32,961) BMD, and from the arcOGEN consortium for three OA phenotypes (hip, ncases=3,498; knee, ncases=3,266; hip and/or knee, ncases=7,410; ncontrols=11,009). Performing LD score regression we found a significant genetic correlation between the combined OA phenotype (hip and/or knee) and lumbar spine BMD (rg=0.18, P = 2.23 × 10−2), which may be driven by the presence of spinal osteophytes. We identified 143 variants with evidence for cross-phenotype association which we took forward for replication in independent large-scale OA datasets, and subsequent meta-analysis with arcOGEN for a total sample size of up to 23,425 cases and 236,814 controls. We found robustly replicating evidence for association with OA at rs12901071 (OR 1.08 95% CI 1.05–1.11, Pmeta=3.12 × 10−10), an intronic variant in the SMAD3 gene, which is known to play a role in bone remodeling and cartilage maintenance. We were able to confirm expression of SMAD3 in intact and degraded cartilage of the knee and hip. Our findings provide the first systematic evaluation of pleiotropy between OA and BMD, highlight genes with biological relevance to both traits, and establish a robust new OA genetic risk locus at SMAD3.

Objectives Osteoarthritis (OA) has a complex aetiology with a strong genetic component. Genome-wide association studies implicate several nuclear genes in the aetiology, but a major component of the heritability has yet to be defined at the molecular level. Initial studies implicate maternally inherited variants of mitochondrial DNA (mtDNA) in subgroups of patients with OA based on gender and specific joint involvement, but these findings have not been replicated. Methods The authors studied 138 maternally inherited mtDNA variants genotyped in a two cohort genetic association study across a total of 7393 OA cases from the arcOGEN consortium and 5122 controls genotyped in the Wellcome Trust Case Control consortium 2 study. Results Following data quality control we examined 48 mtDNA variants that were common in cohort 1 and cohort 2, and found no association with OA. None of the phenotypic subgroups previously associated with mtDNA haplogroups were associated in this study. Conclusions We were not able to replicate previously published findings in the largest mtDNA association study to date. The evidence linking OA to mtDNA is not compelling at present.

Strategies of tissue engineering, regenerative medicine and cell therapy represent a new and emerging way of treating hip disease. This chapter considers relevant cell types, whether to be used as a therapy or as the target of a therapy. It discusses the types of disease and approach where benefit might be expected and reviews the published clinical evidence.

OBJECTIVES: The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. METHODS: The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent. RESULTS: None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. CONCLUSIONS: Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity. Ann Rheum Dis

BACKGROUND: Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. METHODS: We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. FINDINGS: We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. INTERPRETATION: Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. FUNDING: arcOGEN was funded by a special purpose grant from Arthritis Research UK.

There continues to be some dissatisfaction with the function of total knee arthroplasties (TKA). "Mid-range instability" has been linked to multi-radius femoral components allowing transient ligament slackness and instability during knee flexion. Single-radius designs have been introduced to avoid this. We compared the kinematics and stability of eight natural knees versus multi-radius and single-radius TKAs in vitro. The loading conditions imposed across the range of active knee extension were anterior-posterior drawer forces, internal-external rotation torques, and varus-valgus moments. Significant differences were not found between the biomechanical behavior of the two TKAs. Both were significantly different from the natural knee in allowing greater anterior drawer laxity near extension, probably caused by excision of the anterior cruciate ligament, but no difference occurred beyond 30° flexion. No differences were found for any of the other degrees-of-freedom of movement. A geometric analysis suggested that the multi-radius design may tense the MCL more than the single-radius in mid-flexion, contrary to expectation. These kinematic and stability tests did not find mid-range instability of the knees, and so they could not demonstrate enhanced mid-range stability of the single-radius TKA over the older multi-radius implant. This suggests that mid-range instability may relate to unrecognized ligament laxity during surgery, rather than being inherent to a specific feature of implant design.

Osteoarthritis is a common disorder in which there is not only extensive degeneration but also an aberrant attempt at repair in joints. Stem cell therapy could provide a permanent, biological solution, with all sources of stem cells (embryonic, fetal and adult) showing some degree of potential. Mesenchymal stromal/stem cells, however, appear to be the leading candidates because of their ability to be sourced from many or all joint tissues. They may also modulate the immune response of individuals, in a manner influenced by local factors. This biological behavior of stem cells renders the application of regulatory standardizations challenging in comparison to pharmaceutical therapies. However, this would not be an issue if endogenous stem cells were activated to effect repair of an arthritic joint.

OBJECTIVES: Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component. METHODS: A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets. RESULTS: With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p=9.2 x 10), thereby confirming its role as a susceptibility locus for OA. CONCLUSION: The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, beta), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment. [KEYWORDS: Adult, Aged, Aged, 80 and over, Chromosomes, Human, Pair 7/ genetics, Female, Gene Expression Profiling/methods, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Osteoarthritis, Knee/ genetics, Phenotype, Polymorphism, Single Nucleotide, Young Adult]

Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% confidence interval] 1.17 [1.11-1.23], p = 2.1 x 10(-8)) across a total of 19,041 OA cases and 24,504 controls of European descent. This risk locus represents the third established signal for OA overall. MCF2L regulates a nerve growth factor (NGF), and treatment with a humanized monoclonal antibody against NGF is associated with reduction in pain and improvement in function for knee OA patients.

Malalignment may contribute to early prosthesis failure through point loading and premature polyethylene wear. Femoral resection requires for distal planar resection contingent upon correct rotation and coronal alignment. Using a standard model, we have examined the influence of differing femoral entry points and rotations upon final femoral component positioning. A graphical method and navigation system independently quantified the individual and combined impact of these variables, in 3 planes. Nine permutations were assessed with reference to neutral rotation and a central entry point. The graphical results were corroborated by the navigation analyses. We found that external rotation and a superolateral entry point introduced the greatest error in final component positioning. We have identified a safe envelope for femoral rod positioning and recommend that the rotational alignment is determined before distal bone resection.

Background. GPs have to respond to conflicting policy developments. As gatekeeper they are supposed to manage the growing demand for specialist services and as patient advocate they should be responsive to patients' preferences. We used an innovative approach to develop a referral guideline for patients with chronic knee pain that explicitly incorporates patients' preferences.\ud \ud Methods. A guideline development group of 12 members including patients, GPs, orthopaedic surgeons and other health care professionals used formal consensus development informed by systematic evidence reviews. They rated the appropriateness of referral for 108 case scenarios describing patients according to symptom severity, age, body mass, co-morbidity and referral preference. Appropriateness was expressed on scale from 1 (‘strongly disagree’) to 9 (‘strongly agree’).\ud \ud Results. Ratings of referral appropriateness were strongly influenced by symptom severity and patients' referral preferences. The influence of other patient characteristics was small. There was consensus that patients with severe knee symptoms who want to be referred should be referred and that patient with moderate or mild symptoms and strong preference against referral should not be referred. Referral preference had a greater impact on the ratings of referral appropriateness when symptoms were moderate or severe than when symptoms were mild.\ud \ud Conclusions. Referral decisions for patients with osteoarthritis of the knee should only be guided by symptom severity and patients' referral preferences. The guideline development group seemed to have given priority to avoiding inefficient resource use in patients with mild symptoms and to respecting patient autonomy in patients with severe symptoms.

Background: the presence of osteoporosis in patients with hip and knee osteoarthritis (OA) has important implications for understanding disease progression and providing optimal surgical and medical management. Objective: to determine the prevalence of osteoporosis among patients with osteoarthritis awaiting total knee arthroplasty or total hip arthroplasty aged between 65 and 80 years. Design: cross-sectional observational study. Setting: tertiary referral centre in Newcastle upon Tyne, UK. Subjects: patients with osteoarthritis awaiting total knee hip arthroplasty aged between 65 and 80 years. Methods: lumbar spine, bilateral femoral and forearm bone mineral density (BMD) measurements were obtained using dualenergy X-ray absorptiometry. Results: the cohort consisted of 199 patients with a mean age of 72 years (SD 4), and 113 (57%) were women. The overall rate of osteoporosis at any site was 23% (46/199) and a further 43% (85/199) of patients would have been classified as osteopaenic according to World Health Organization criteria. Osteoporosis was more commonly detected in the forearm (14%) than the lumbar spine (8.5%) and proximal femur of the index side (8.2%). Conclusions: in summary, a significant proportion of patients with end-stage OA have osteoporosis but this diagnosis may be missed unless BMD measurements are performed at sites distant from joints affected by OA.

Background Resurfacing is a popular alternative to a standard hip replacement in young arthritic patients. Despite bone preservation around the femoral component, there is little information regard...

Ti alloys are commonly used as dental and orthopaedic implants. It has been shown that surface topography can influence cell genesis, behaviour and growth. In this work we have electropolished and micro-patterned Ti-6Al-4V alloy to study the effect of surface topography on cell morphology. Electroetching was carried out in a flat cell under galvanostatic polarisation of 5.0 V and 9.0 V vs. SCE, using a 3.0 M H2SO4 - methanol electrolyte. Electropolishing conditions were achieved when the overpotential was 9.0 V. Micropatterning of Ti alloy substrates was carried out at the same potentials by etching through mask; a methanol stable SU-8 photoresist was used for this purpose. Human mesenchymal stem cells were seeded and grown on these substrates. It was found that surface nano and micro scale topography influenced cell numbers and morphology, respectively.