Objectives. The molecular mechanism of rheumatoid arthritis (RA) remains elusive. We conducted a protein-protein interaction network-based integrative analysis of genome-wide association studies (GWAS) and gene expression profiles of RA. Methods. We first performed a dense search of RA-associated gene modules by integrating a large GWAS meta-analysis dataset (containing 5539 RA patients and 20 169 healthy controls), protein interaction network and gene expression profiles of RA synovium and peripheral blood mononuclear cells (PBMCs). Gene ontology (GO) enrichment analysis was conducted by DAVID. The protein association networks of gene modules were generated by STRING. Results. For RA synovium, the top-ranked gene module is HLA-A, containing TAP2, HLA-A, HLA-C, TAPBP and LILRB1 genes. For RA PBMCs, the top-ranked gene module is GRB7, consisting of HLA-DRB5, HLA-DRA, GRB7, CD63 and KIT genes. Functional enrichment analysis identified three significant GO terms for RA synovium, including antigen processing and presentation of peptide antigen via major histocompatibility complex class I (false discovery rate (FDR) = 4.86 × 10 – 4), antigen processing and presentation of peptide antigen (FDR = 2.33 × 10 – 3) and eukaryotic translation initiation factor 4F complex (FDR = 2.52 × 10 – 2). Conclusion. This study reported several RA-associated gene modules and their functional association networks. Cite this article: X. Xiao, J. Hao, Y. Wen, W. Wang, X. Guo, F. Zhang. Genome-wide association studies and gene expression profiles of rheumatoid arthritis: an analysis. Bone Joint Res 2016;5:314–319. DOI: 10.1302/2046-3758.57.2000502

The long-term clinical and radiological results of 63 uncemented Low Contact Stress (LCS) total knee replacements in 47 patients with rheumatoid arthritis were reviewed. The average age at the time of surgery was 69 years (53–81). At a mean follow up of 22 years (20–25), 12 patients (17 knees) were alive, 27 (36 knees) had died, and 8 patients (10 knees) were lost to follow-up. Revision was necessary in seven patients (7 knees) (11.1%) at mean 12.1 years following surgery. Four revisions were performed due to meniscal bearing wear, two for collapse of the tibial component, and one for aseptic loosening. Evidence of post-operative infection occurred in two knees (3.2%) within 6 weeks of surgery but resolved with antibiotics. Within the group of deceased patients, five had undergone revision (included in total revisions) but otherwise the primary implant remained in vivo. For all living patients, the mean Oxford Knee Score (/48) was 30.2 (16–41) at latest follow up at mean 19.5 years (15–24.7) following surgery. Mean active flexion was 105 degrees (90–150) at this time point. Our recorded survival rate of the uncemented LCS total knee replacements in patients with rheumatoid arthritis was therefore 88.9% at mean 22 years, or worst-case survival of 73.0% if patients lost to follow-up were considered failures. From a review of the literature and as far as we are aware, this study represents the longest follow up of any uncemented knee arthroplasty performed in a cohort of patients with rheumatoid arthritis

We evaluated histologically samples of synovial tissue from the knees of 50 patients with rheumatoid arthritis (RA). The samples were taken during revision for aseptic loosening. The findings were compared with those in 64 knees with osteoarthritis (OA) and aseptic loosening and in 18 knees with RA without loosening. The last group had been revised because of failure of the inlay or the coupling system of a constrained prosthesis. All the patients had had a total ventral synovectomy before implantation of the primary prosthesis. In all three groups a foreign-body reaction and lymphocellular infiltration were seen in more than 80% of the tissue samples. Deposits of fibrin were observed in about one-third to one-half of the knees in all groups. Typical signs of the reactivation of RA such as rheumatoid necrosis and/or proliferation of synovial stromal cells were found in 26% of knees with RA and loosening, but not in those with OA and loosening and in those with RA without loosening. Our findings show that reactivation of rheumatoid synovitis occurs after total knee replacement and may be a cofactor in aseptic loosening in patients with RA

We have measured the concentration of cartilage-derived retinoic-acid-sensitive protein (CD-RAP) in synovial fluid (SF) from the knees of 49 patients with osteoarthritis (OA) and 79 with rheumatoid arthritis (RA) in order to investigate the correlation between the type of joint disease and level of CD-RAP. The mean concentration of CD-RAP in synovial fluid was significantly higher in OA than in RA. The level of CD-RAP in the group of patients with mild OA was significantly higher than in the moderate or severe groups and that in the group with mild RA was also significantly higher than in the other RA groups and decreased with progression of the disease. Immunohistochemical studies showed expression of CD-RAP in the cytoplasm of chondrocytes in newly-formed fibrocartilage. Since CD-RAP is mainly produced in young and proliferating chondrocytes, our results suggest that the level of CD-RAP in synovial fluid reflects remodelling of articular cartilage and may be used as a marker to estimate objectively the restorative reaction of chondrocytes

Summary Statement. For RA patients undergoing TKR, the gain in function at 6 months following surgery is less than that experienced by OA patients; for THR, however, gains are similar in OA and RA patients. Introduction. Total joint replacement (TJR) is commonly used in rheumatoid arthritis (RA) patients and yet little information is available to quantify their functional gain following surgery and how it differs from what the osteoarthritis (OA) population experiences. Therefore, we examined 6-month functional outcomes of TJR in a population-based observational cohort of RA and OA patients who underwent total hip (THR) or knee (TKR) replacement. Methods. Patients undergoing primary TKR from 7/1/11 through 12/3/12 were identified from the FORCE-TJR national research consortium which enrolls patients from 111 surgeons across 27 states in the US. The registry gathers data from patients, surgeons and hospitals on patient demographics, underlying type of arthritis, operative joint severity based on the estimated Western Ontario and McMaster Universities Arthritis Index (WOMAC) using the Hip and Knee Disability and Osteoarthritis Outcome Scores, function based on the Short Form 36 Physical Component Score (PCS), and mental health using the SF-36 Mental Component Score (MCS). Descriptive statistics were performed. Results. There were 95 RA and 991 OA patients who underwent primary TKR, and 59 RA and 740 OA patients who underwent primary THR. Among TKR patients, RA patients are more likely to be women (68% vs. 61%), nonwhite (17% vs. 9%), unmarried (59% vs. 70%) with an annual income of ≤$45,000 (57% vs. 39%) as well as lower baseline emotional health (48 vs. 52) and functioning (31 vs 33). Among THR patients, RA patients are more likely to be nonwhite (18% vs. 8%), unmarried (66% vs. 69%) with an annual income of ≤$45,000 (54% vs. 34%) as well as lower baseline emotional health (46 vs. 51) and functioning (30 vs 32). RA patients undergoing TKR have less functional gain 6 months post-surgery (6.6 vs. 9.7; p=0.002) as compared to OA patients. In contrast, RA patients who undergo THR have similar functional gain (11.6 vs. 13.8; p=0.13) as compared to OA patients. Discussion/Conclusion. RA patients have less functional improvement as compared to those with OA when undergoing TKR but similar gains when undergoing THR

We describe a model which can be used for in vitro biocompatibility assays of biomaterials. We studied the in vitro response of human osteoarthritis or rheumatoid arthritis fibroblast-like synoviocytes to Al. 2. O. 3. or ZrO. 2. particles by analyzing the production of interleukin-1 (IL-1) and interleukin-6 (IL-6) and the metabolism of arachidonic acid via lipoxygenase and cyclo-oxygenase pathways. Our results show that, in these cells and under our experimental conditions, Al. 2. O. 3. and ZrO. 2. did not significantly modify the synthesis of IL-1 and IL-6 or the metabolism of arachidonic acid

We have compared the concentrations of stromal-cell-derived factor-1 (SDF-1), matrix metalloproteinase-1 (MMP-1), MMP-9 and MMP-13 in serum before and after synovectomy or total knee replacement (TKR). We confirmed the presence of SDF-1 and its receptor CXCR4 in the synovium and articular cartilage by immunohistochemistry. We established chondrocytes by using mutant CXCR4 to block the release of MMPs.

The level of SDF-1 was decreased 5.1- and 6.7-fold in the serum of patients with OA and RA respectively, after synovectomy compared with that before surgery. MMP-9 and MMP-13 were decreased in patients with OA and RA after synovectomy. We detected SDF-1 in the synovium and the bone marrow but not in cartilage. CXCR4 was detected in articular cartilage. SDF-1 increased the release of MMP-9 and MMP-13 from chondrocytes in a dose-dependent manner. The mutant CXCR4 blocked the release of MMP-9 and MMP-13 from chondrocytes by retrovirus vector.

Synovectomy is effective in patients with OA or RA because SDF-1, which can regulate the release of MMP-9 and MMP-13 from articular chondrocytes for breakdown of cartilage, is removed by the operation.

Total Knee Arthroplasty (TKA) improves the quality of life of osteoarthritic and rheumatoid arthritis patients, however, is associated with moderate to severe postoperative pain. There are multiple methods of managing postoperative pain that include epidural anesthesia but it prevents early mobilization and results in postoperative hypotension and spinal infection. Controlling local pain pathways through intra-articular administration of analgesics is a novel method and is inexpensive and simple. Hence, we assess the effects of postoperative epidural bupivacaine injection along with intra-articular injection in total knee replacement patients. The methodology included 100 patients undergoing TKA randomly divided into two groups, one administered with only epidural bupivacaine injection and the other with intra-articular cocktail injection. The results were measured based on a 10-point pain assessment scale, knee's range of motion (ROM), and Lysholm knee score. The VAS score was lower in the intra-articular cocktail group compared to the bupivacaine injection group until the end of 1-week post-administration (p<0.01). Among inter-group comparisons, we observed that the range of motion was significantly more in cocktail injection as compared to the bupivacaine group till the end of one week (p<0.05). Lysholm's score was significantly more in cocktail injection as compared to the bupivacaine group till the end of one week (p<0.05). Our study showed that both epidural bupivacaine injection and intra-articular injection were effective in reducing pain after TKA and have a comparable functional outcome at the end of 4 weeks follow up. However, the pain relief was faster in cases with intra-articular injection, providing the opportunity for early rehabilitation. Thus, we recommend the use of intra-articular cocktail injection for postoperative management of pain after total knee arthroplasty, which enables early rehabilitation and faster functional recovery of these patients

A hot swollen joint is a commonly encountered condition in clinical practice. With a broad range of differentials, septic arthritis (SA) is perhaps one of the most concerning. Treated by culture-specific antibiotics and arthroscopic lavage, some patients require multiple washouts. We aimed to determine:. (1) What are the risk factors for development of SA?. (2) What are the risk factors for repeat washout in SA patients?. (3) What are the important clinical differences between a periprosthetic joint infection (PJI) and SA cohort?. All patients presenting to the emergency department, orthopaedic, and rheumatology clinics between January 2020 to January 2021 with a hot, swollen joint were retrospectively evaluated. Patients with previous trauma on the ipsilateral joint, with data missing from their medical records in any of the variables required for analysis, <24 months follow-up were excluded. Variables of interest in the three-month period preceding the diagnosis of SA were compared between SA and non-SA patients. Factors with a p-value of p<0.100 in univariate analysis were included in a stepwise multivariate logistic regression model. Similar analyses were performed to compare SA patients with multiple washouts with those needing one washout. Demographical and clinical data for PJI patients were collected to delineate important differences with SA cohort. 211 patients were included (SA:28;PJI:24;pseudogout:32;gout:26;others:101). Multivariate analysis showed rheumatoid arthritis (RA), skin infection, and liver disease were risk factors for SA. Amongst patients with septic arthritis, multivariate analysis showed that WBC levels above normal limits (3.6-10.5×109 cells/L) and RA were risk factors for multiple washouts. Between the SA and PJI cohorts, BMI (p=0.002) was significantly lower in the former, whilst WBC level (p=0.023) and CRP (p<0.0001) was significantly higher in the former. Early diagnosis of septic arthritis requires understanding the risk factors, namely RA, skin infection, and liver disease. Considering PJI and septic arthritis as the same entity can lead to wrong clinical judgement, and clinicians should be aware of important differences. We believe that the models in this study are of prognostic value to clinicians who are presented with the common presenting compliant of a hot swollen joint

Abstract. Objectives. The aim of this study was to investigate whether mechanical loading induced by physical activity can reduce risk of sarcopenia in middle-aged adults. Methods. This was a longitudinal study based on a subset of UK Biobank data consisting of 1,918 participants (902 men and 1,016 women, mean age 56 years) who had no sarcopenia at baseline (assessed between 2006 and 2010). The participants were assessed again after 6 years at follow-up, and were categorized into no sarcopenia, probable sarcopenia, or sarcopenia according to the definition and algorithm developed in 2018 by European Working Group on Sarcopenia in Older People (EWGSOP). Physical activity was assessed at a time between baseline and follow-up using 7-day acceleration data obtained from wrist worn accelerometers. Raw acceleration data were then analysed to study the mechanical loading of physical activity at different intensities (i.e. very light, light, moderate-to-vigorous). Multinominal logistic regression was employed to examine the association between the incidence of sarcopenia and physical activity loading, between baseline and follow up, controlled for other factors at baseline including age, gender, BMI, smoking status, intake of alcohol, vitamin D and calcium, history of rheumatoid arthritis, osteoarthritis, secondary osteoporosis, and type 2 diabetes. Results. Among the 1918 participants with no sarcopenia at baseline, 230 (69 men and 161 women) developed probable sarcopenia and 37 (14 men and 23 women) developed sarcopenia at follow-up. Physical activity loading at moderate-to-vigorous intensity was higher in men (p<0.05), while women had higher physical activity loading at very light intensity (p<0.05). No significant difference was found in physical activity loading at light intensity between men and women (p>0.05). Logistic regression models showed that increase in physical activity loading at moderate-to-vigorous intensity significantly reduced the risk of sarcopenia (odds ratio = 0.368, p<0.05), but not probable sarcopenia (odds ratio = 0.974, p>0.05), while loading at light or very light activity intensity were not associated with the risk of sarcopenia or probable sarcopenia (p>0.05). Conclusion. Loading of physical activity at moderate-to-vigorous intensity could reduce risk of sarcopenia in middle-aged adults. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Purpose. To evaluate the clinical results of arthroscopic repair and open Ahlgren Larsson method in patients with chronic lateral ankle instability. Methods. We retrospectively evaluated 87 patients who were operated in our clinic between 2010 and 2018 with the diagnosis of chronic lateral ankle instability. 16 patients with osteochondral lesion, 5 patients with rheumatoid arthritis, 4 patients with ankle fractures of the same side, 2 patients with a history of active or previous malignancy were excluded. Preoperative and postoperative clinical evaluations were performed with AOFAS ankle-hindfoot score, FAOS and VAS scores. Results. Sixty patients with chronic lateral ankle instability were evaluated. 28 patients, treated with Ahlgren-Larsson method and 32 patients, treated with arthroscopic repair. 36 of the patients were female and 24 were male; the mean age of the arthroscopy group was 44 ± 9; the mean age of the open surgery group was 46 ± 11. There was no significant difference between the groups in terms of demographic features (age, sex, VKI). Postoperative clinical improvement was observed in both groups. There was no statistically significant difference between the groups in terms of functionality. However, there was a statistically significant difference in pain and satisfaction of VAS in favor of arthroscopy group. Conclusions. Ahlgren-Larsson method and arthroscopic repair technique are safe and effective for chronic lateral ankle instability. Arthroscopic technique may be preferred for pain and patient satisfaction as it is less invasive and less morbid

Background. The current average tariff of a total knee replacement (TKR) is £5500. The approximate cost of each knee prosthesis is £2500. Therefore, length of patient stay (LOS) and the cost of patient rehabilitation influence the total costs significantly. Previous studies have shown a mean LOS of between 5 and 9.4 days for patients undergoing primary unilateral TKR but none looked at the factors influencing length of stay following bilateral primary total knee replacements (BTKR) at the same sitting. Objectives. To identify significant factors that influence the LOS following BTKR at the same sitting in a single centre in the UK. Methods. This was a retrospective single-centre study performed at the Princess Royal Hospital which performed a total of 25 BTKR. Surgical and patient factors that may influence LOS were recorded and analysed. Results. The mean LOS was 10 days with a median of 9 days. 64% were discharged within 10 days. Those staying longer were classified as long stayers. Being a female (0.65, p< 0.05), having a higher Charlson index (0.68, p< 0.05) and having a post-operative blood transfusion (0.59, p< 0.05) were the only significant factors that influenced LOS. Post-operative acute kidney injury (AKI), underlying diagnosis such as rheumatoid arthritis, BMI, age, worse pre-operative oxford knee scores and type of implant did not influence LOS. Conclusion. Factors influencing LOS following BTKR shown in our study seems to be the same as those influencing unilateral TKRs as identified in the literature. This should be taken into consideration when comparing unilateral versus bilateral TKR results as well as when planning a local arthroplasty service

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

Musculoskeletal diseases are leading causes of disability, morbidity and economic loss across the globe today. Yet for much of the world's population access to cheap, safe and effective intervention is lacking, while others choose not to accept best practice and best evidence, or significantly more expensive treatment. Great advances have been made in some diseases like rheumatoid arthritis, but the cost of many new treatments is unaffordable, and individuals, insurance and governments struggle to, or cannot fund it. Anchor bias and politics determines national policies and research funding, often favouring other illnesses while musculoskeletal disorders lack the support proportional to their frequency and impact. This is not appreciated by policy makers and governments, and the consequences of lack of care or poor-quality care. The need has never been greater for a treatment for osteoarthritis, the most common disease in the world; but the search for a cure needs funding, and if discovered, who will pay for it?

Summary. Hyaluronan suppressed lipopolysaccharide-stimulated prostaglandin E. 2. production via intercellular adhesion molecule-1 through down-regulation of nuclear factor-κB. Administration of hyaluronan into rheumatoid joints may decrease prostaglandin E. 2. production by activated macrophages, which could result in improvement of arthritic pain. Introduction. Prostaglandin E. 2. (PGE. 2. ) is one of the key mediators of inflammation in rheumatoid arthritis (RA) joints. Intra-articular injection of high molecular weight hyaluronan (HA) into RA knee joints relieves arthritic pain. Although HA has been shown to inhibit PGE. 2. production in cytokine-stimulated synovial fibroblasts, it remains unclear how HA suppresses PGE. 2. production in catabolically activated cells. Furthermore, HA effect on macrophages has rarely been investigated in spite of their contribution to RA joint pathology. Objectives. This study was aimed to investigate the inhibitory mechanism of HA on lipopolysaccharide (LPS)-stimulated PGE. 2. in U937 human macrophage culture system. Methods. With or without pretreatment with one of HA, NS-398, and BAY11-7085, differentiated U937 macrophages were stimulated with LPS. In another set of experiments, the cells were incubated with anti-ICAM-1 antibody or non-specific IgG before pretreatment with HA. PGE. 2. concentrations of the cell-free supernatants were determined using an enzyme-linked immunosorbent assay. The cell lysates and nuclear extracts were prepared for immunoblot analysis. HA binding to ICAM-1 was evaluated by fluorescence microscopic analysis. Results. Stimulation of U937 macrophages with LPS enhanced PGE. 2. production in association with increased protein levels of cyclooxygenase-2 (COX-2). Pretreatment with HA of 2,700 kDa resulted in suppression of LPS-induced COX-2, leading to a decrease in PGE. 2. production. While LPS activated NF-κB pathway, inhibition studies using BAY11-7085 revealed the requirement of NF-κB for LPS-stimulated PGE. 2. production. HA down-regulated the phosphorylation and nuclear translocation of NF-κB by LPS. Fluorescence cytochemistry demonstrated that HA bound to ICAM-1 on U937 macrophages. Anti-ICAM-1 antibody reversed the inhibitory effects of HA on LPS-activated PGE. 2. , COX-2, and NF-κB. Conclusion. These results clearly demonstrated that HA suppressed LPS-stimulated PGE2 production via ICAM-1 through down-regulation of NF-κB. Clinical administration of high molecular weight HA into RA joints may decrease PGE2 production by activated macrophages, which could result in improvement of arthritic pain

Summary. Methotrexate chemotherapy (commonly used in treating cancers and rheumatoid arthritis) creates an inflammatory condition in bone, decreasing osteogenesis, enhancing adipogenesis, increasing osteoclastogenesis, leading to bone loss and marrow adiposity; treatment with fish oil or folinic acid counteracts these negative effects and prevents bone loss. Introduction. Chemotherapy with anti-metabolite methotrexate (MTX) is commonly used in treating cancers and rheumatoid arthritis; however it is known to cause bone loss for which currently there are no adjunct preventative treatments. Methods and Materials. Using a rat model, this study investigated the damaging effects in bones caused by daily MTX injections (0.75mg/kg) for 5 consecutive days (mimicking induction phase treatment for childhood leukaemia) and also the potential protective benefits of omega-3 fatty acid-rich fish oil at different doses (0.25, 0.5 or 0.75 mL/100g BW) in comparison to antidote folinic acid (given i.p at 0.75mg/kg 6 hours post MTX, which is clinically used to reduce MTX toxicities in soft tissues). Results. Histological analysis showed that MTX significantly reduced primary spongiosa bone height and metaphyseal trabecular bone volume. MTX also significantly reduced density of osteoblasts at the secondary spongiosa. Ex vivo differentiation assays with bone marrow stromal cell populations of treated rats revealed a significant reduction in osteogenic differentiation but an increase in adipogenesis. Consistently, RT-PCR gene expression study within the stromal cell population revealed a lower expression of osteogenic transcription factors Runx2 and Osx and bone matrix protein osteocalcin but a significantly upregulated adipogenesis-related genes FABP4 and PPARγ, indicating that MTX chemotherapy induces a switch in the differentiation potential towards adipogenesis at the expense of osteogenesis. MTX increased the density of osteoclasts within the metaphyseal bone as revealed by histological analysis and osteoclast precursor cell pool as shown by ex vivo osteoclastogenesis assay with bone marrow samples. Consistently, mRNA expression of proinflammatory and osteoclastogenic cytokines IL-1, IL-6, TNF-α, and the RANKL/OPG ratio were significantly upregulated by MTX. Supplementary treatment with fish oil (0.5mL/100g BW) or folinic acid significantly preserved metaphyseal trabecular bone volume, osteoblast density, and bone marrow stromal cell osteogenic differentiation and suppressed MTX-induced adipogenesis. These supplements also prevented MTX-induced increased osteoclast density, osteoclastogenesis, and expression of proinflammatory and osteoclastogenic cytokines. Conclusion. These results suggest that MTX chemotherapy creates an inflammatory condition in bone resulting in increased osteoclast formation and decreased osteoblast formation thus leading to bone loss, and that supplementary treatment with fish oil at 0.5mL/100g BW or folinic acid counteract these negative effects, helping to conserve bone formation, suppress bone resorption and bone marrow adiposity, and thus prevent bone loss during MTX chemotherapy

Introduction. NF-κB transcription factors regulate a number of genes that are activated under stress conditions. Blockage of the the canonical NF-κB pathway has been emerged as a possible strategy to cure osteoarthritis and rheumatoid arthritis. However, the roles of κNF-B in normal skeletal physiology are largely unknown owing to the lack of suitable animal models. Here, we investigated the function of canonical κNF-B pathway in the cartilaginous skeleton by ablating Nemo (NF-κB essential modulator) in chondrocytes using the Col2a1 transgene. Methods. Mice were analyzed by skeletal staining, histology, proliferation and apoptosis assays at various stages. Histochemistry, GAG assay and immunohistochemistry were utilized to assess the impact of NEMO-deficiency in cytokine-induced cartilage degradation of hip explants. To identify genes regulated through the canonical NF-κB pathway in response to injury, an ex vivo hip avulsion model was applied. 24 genes known to be induced early following cartilage injury were assessed in wildtype and mutant hips by RT-PCR. Time lapse photography was used to investigate chondrocyte migration in vitro. Atomic force microscopy (AFM) was applied to assess biomechanical properties of the cartilage. Pathological changes of articular cartilage were scored in aged joints. Results. Mutant mice exhibited moderate dwarfism postnatally characterized by disorganized growth plate, abnormal chondrocyte proliferation, apoptosis and migration. AFM indentation experiments showed no changes in biomechanical properties of the mutant growth plate compared with control. Exposure of aggrecan degradation neoepitopes and release of GAGs were less pronounced in mutant hip explants stimulated by cytokines. Of the 24 genes regulated 4h following injury in wildtype hips, only Arginase-1 was suppressed in the mutant hips, while the expression levels of most other inflammatory response genes e.g. TSG-6, NOS2, COX2, IL6 and IL1b were unaffected. A small number of genes, IL-18, MMP-3 and Has-2 were further upregulated upon injury in Nemo-deficient compared with wildtype hips. Aging mutant mice showed signs of osteoarthritis comparable to wildtype. Conclusion. Nemo-deficient mice have demonstrated an important role for canonical NF-κB signaling in skeletal growth by modulating chondrocyte behavior. Even though the catabolic effects of pro-inflammatory cytokines in cartilage could be partially eased by blocking the canonical NF-κB pathway, canonical NF-κB signaling seems to play only a minor role in injury-induced inflammatory gene expression and the development of spontaneous OA

Introduction. Human bone marrow-derived mesenchymal stem cells (hBMSCs) can adopt either an immune suppressive or stimulative phenotype in response to cytokines and pathogen-associated molecular patterns (PAMPs). It is known that the glycoprotein CD24 allows for the discrimination between PAMPs and DAMPs in dendritic cells. We were able to show previously that CD24 is expressed by hBMSCs and found that its overexpression leads to the downregulation of NF-kB-regulated genes, as well as induction of the anti-inflammatory TGF beta. In the present study the influence of various PAMPs and cytokines on the expression of CD24 in hBMSCs was analysed. Furthermore, it was tested whether in vivo-CD24-positive (CD24+) and in vivo-CD24-negative (CD24-) hBMSCs differ in regard to classical hBMSC or immune-associated surface antigens. Methods. hBMSCs were enriched by density gradient centrifugation, cultured in vitro until passage 3 and subsequently stimulated with PAMPs or cytokines (IFN gamma, TGF beta) before analysing the expression of CD24 via qRT-PCR. Cells expressing CD24 in vivo (CD24+ hBMSCs) were enriched from bone marrow aspirates after density gradient centrifugation by the use of magnetic-associated cell sorting (MACS). Successful enrichment was evaluated by flow cytometric analysis. The enriched cells were subsequently cultured in comparison to the CD24-depleted cell population (CD24- hBMSCs) under identical conditions. The expression of various cell surface markers was compared between these two populations using flow cytometry. Results. All tested PAMPs, as well as IFN gamma led to the downregulation of CD24 in comparison to non-stimulated control cells. In contrast, stimulation with TGF beta resulted in an increased CD24 expression. CD24-positive hBMSCs were successfully enriched via MACS and cultured in vitro. While there was no difference between the expression of classical hBMSC surface antigens between the two cell populations, the CD24+ population had a significantly higher expression of PD-L1 than the CD24- population. Discussion. hBMSCs are capable of ameliorating autoimmune processes by inducing T-cell anergy. Polymorphisms in CD24 are associated with the development of autoimmune diseases. In this context it is worth of note that CD24+ hBMSCs show an elevated expression of PD-L1. PD-L1 is a molecule that can induce anergy in T cells by binding to PD-1 thereby dampening the immune response to self antigens. Therefore, hBMSCs with strong CD24-expression might be beneficial in treating autoimmune diseases such as rheumatoid arthritis. PAMPs and IFN-gamma lead to the downregulation of CD24, which may strip hBMSCs of their ability to induce T cell anergy and to dampen immune responses to self antigens

Introduction. Prosthetic joint infection (PJI) is an uncommon but serious complication of hip replacement. A recent systematic review of patient risk factors for PJI identified male gender, smoking status, increasing BMI, steroid use, previous joint surgery and comorbidities of diabetes, rheumatoid arthritis and depression as risk factors for developing PJI. Limitations of the current literature include the short term follow up of most published studies. We investigated the role of patient, surgical and healthcare factors on the risk of revision of a primary hip replacement for PJI at different time-points in the post-operative follow-up. It is important that those risk factors are identified so that patients can be appropriately counselled according to their individual risk profile prior to surgery and modifiable factors can be addressed to reduce the risk of PJI at an individual and healthcare system level. Materials and Methods. Primary hip replacements and subsequent revision procedures performed for PJI from 2003–2014 were identified from the National Joint Registry (NJR). Patient (age, gender, ASA grade, BMI), perioperative (surgical indication, type of anaesthesia, thromboprophylaxis regime, surgical approach, hip replacement and bearing surface and use of femoral or acetabular bone graft) and healthcare system characteristics (surgeon grade, surgical volume) were linked with data from Hospital Episode Statistics to obtain information on specific ethnicity and comorbidities (derived from the Charlson index). Multilevel piecewise exponential non-proportional hazards models were used to estimate their effects at different post-operative periods (0–3 months, 3–6 months, 6–12 months, 12–24 and >24 months post-operation). Results. The index hip replacements consisted of 623,253 primaries with 2,705 subsequently revised for PJI, 14% within 3 months, 8% between 3–6 months, 14% between 6–12 months, 22% between 1–2 years and 42% ≥2 years after the index procedure. Risk factors for revision of PJI included male gender, high BMI, high ASA grade and younger age. Their effects were period-specific. Patients with chronic pulmonary disease, diabetes or dementia had high early risk of revision for PJI, as did patients operated for a fractured neck of femur (<3 months). Metal-on-metal bearings (>12 months) and lateral surgical approach (≥3 months) also influenced the mid- and long-term revision risk for PJI. No or modest associations were found with the operating surgeon grade, surgical volume and hospital surgical volume. Conclusion. The effects of patient, perioperative and healthcare system risk factors for PJI after primary hip replacement are time-dependent. Modifiable risk factors such as the type of surgical approach and bearing surface have also been found

Total hip replacement (THR) in young patients has been associated to higher revision rates than in older population. Different conditions may lead to end-stage arthritis of the hip in these patients. We compared the clinical and radiological outcome of two different groups of young and very young patients who underwent a ceramic-on-ceramic THR. 120 hips were prospectively followed for a mean of 10.4 years (range, 5 to 17). 38 patients (46 hips) were less than 30 years old (group 1), and, 68 (74 hips) were between 31 and 40 years old (group 2). Weight (p<0.001) and physical activity level were greater in group 2 (p<0.001). Preoperative function (p=0.03) and range of mobility (p=0.03) were worse in group 1. Primary osteoarthritis was not found in any case. Rheumatoid juvenile arthritis was the most frequent diagnosis in group 1 and avascular necrosis of the femoral head in group 2. A femoral funnel-shaped type 1 according to Dorr was more frequent in group 2 (p=0.04). The same ceramic-on-ceramic uncemented THR was used in all cases. Screws for cup fixation were only used when strictly needed. We analysed the clinical results according to the Merle-D´Aubignè and Postel scale, the postoperative radiological reconstruction of the hip and the radiological appearance of cup loosening. Kaplan-Meier survivorship analysis was used to estimate the cumulative probability of not having a revision surgery. Screw use required to obtain a secured interference fit of the acetabular component was found more frequently in group 1 (p=0.01). Postoperative pain (p=0.002) and function (p=0.002) were better in group 1. Mean acetabular abduction angle of the cup was greater in group 1 (p=0.03) and reconstruction to the hip rotation center according to Ranawat (p=0.01) was better in group 2. Placement of the acetabular component inside the Lewinnek´s zone and stem position were similar in both groups. No hips were revised due to complications related to ceramic or to stem loosening. Three cups were revised for aseptic loosening in group 1 and four in group 2. The survival rate for cup aseptic loosening at 15 years was 92.3% (95% CI: 83.7 to 100) for group 1 and 93.1% (95% CI: 85.3 to 99.9) for group 2 (Log rank, p=0.88). Ceramic-on-ceramic uncemented THR is an excellent option for young and very young patients. Despite worse preoperative conditions in patients under the age of 30 years, a similar clinical outcome was found in this series