Inhibition of KDM7A/B histone demethylases restores H3K79 methylation and protects against osteoarthritis.

OBJECTIVES: In osteoarthritis, methylation of lysine 79 on histone H3 (H3K79me), a protective epigenetic mechanism, is reduced. Histone methylation levels are dynamically regulated by histone methyltransferases and demethylases. Here, we aimed to identify which histone demethylases regulate H3K79me in cartilage and investigate whether their targeting protects against osteoarthritis. METHODS: We determined histone demethylase expression in human non-osteoarthritis and osteoarthritis cartilage using qPCR. The role of histone demethylase families and subfamilies on H3K79me was interrogated by treatment of human C28/I2 chondrocytes with pharmacological inhibitors, followed by western blot and immunofluorescence. We performed C28/I2 micromasses to evaluate effects on glycosaminoglycans by Alcian blue staining. Changes in H3K79me after destabilisation of the medial meniscus (DMM) in mice were determined by immunohistochemistry. Daminozide, a KDM2/7 subfamily inhibitor, was intra-articularly injected in mice upon DMM. Histone demethylases targeted by daminozide were individually silenced in chondrocytes to dissect their role on H3K79me and osteoarthritis. RESULTS: We documented the expression signature of histone demethylases in human non-osteoarthritis and osteoarthritis articular cartilage. Inhibition of Jumonji-C demethylase family increased H3K79me in human chondrocytes. Blockade of KDM2/7 histone demethylases with daminozide increased H3K79me and glycosaminoglycans. In mouse articular cartilage, H3K79me decayed rapidly upon induction of joint injury. Early and sustained intra-articular treatment with daminozide enhanced H3K79me and exerted protective effects in mice upon DMM. Individual silencing of KDM7A/B demethylases in human chondrocytes demonstrated that KDM7A/B mediate protective effects of daminozide on H3K79me and osteoarthritis. CONCLUSION: Targeting KDM7A/B histone demethylases could be an attractive strategy to protect joints against osteoarthritis.

Inhibiting thyroid activation in aged human explants prevents mechanical induced detrimental signalling by mitigating metabolic processes.

OBJECTIVES: To investigate whether the deiodinase inhibitor iopanoic acid (IOP) has chondroprotective properties, a mechanical stress induced model of human aged explants was used to test both repeated dosing and slow release of IOP. METHODS: Human osteochondral explants subjected to injurious mechanical stress (65%MS) were treated with IOP or IOP encapsulated in poly lactic-co-glycolic acid-polyethylene glycol nanoparticles (NP-IOP). Changes to cartilage integrity and signalling were determined by Mankin scoring of histology, sulphated glycosaminoglycan (sGAG) release and expression levels of catabolic, anabolic and hypertrophic markers. Subsequently, on a subgroup of samples, RNA sequencing was performed on 65%MS (n = 14) and 65%MS+IOP (n = 7) treated cartilage to identify IOP's mode of action. RESULTS: Damage from injurious mechanical stress was confirmed by increased cartilage surface damage in the Mankin score, increased sGAG release, and consistent upregulation of catabolic markers and downregulation of anabolic markers. IOP and, though less effective, NP-IOP treatment, reduced MMP13 and increased COL2A1 expression. In line with this, IOP and NP-IOP reduced cartilage surface damage induced by 65%MS, while only IOP reduced sGAG release from explants subjected to 65%MS. Lastly, differential expression analysis identified 12 genes in IOP's mode of action to be mainly involved in reducing metabolic processes (INSIG1, DHCR7, FADS1 and ACAT2) and proliferation and differentiation (CTGF, BMP5 and FOXM1). CONCLUSION: Treatment with the deiodinase inhibitor IOP reduced detrimental changes of injurious mechanical stress. In addition, we identified that its mode of action was likely on metabolic processes, cell proliferation and differentiation.

GRAPPA 2019 Research Recipient Awards Report.

A summary of the research conducted by the recipients of the 2019 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Research Awards is presented. Dr. Alla Ishchenko's project was "Role of Metabolomics in Diagnosis, Disease Severity, and Progression in Psoriasis and Psoriatic Arthritis: A 2-year Prospective Pilot Study" and Dr. Zhenrui Shi's project was "Preclinical Analysis of CCR6 and CCL20 in Mouse and Human Joints, Respectively, as Targets of Therapeutic Intervention in Psoriatic Arthritis."

Structural Disease Progression in Axial Spondyloarthritis: Still a Cause for Concern?

PURPOSE OF THE REVIEW: Progressive ankylosis is a feared consequence of long-standing axial spondyloarthritis. We aim to critically review current insights into the effect of therapy, the molecular pathways involved in this process, and to present a model explaining the sequence of events. RECENT FINDINGS: Long-term follow-up data suggest that successful control of inflammation may slow down radiographic progression of disease in axial spondyloarthritis. Structural effects of new therapies such as interleukin-17 targeting need to be further studied. Bone loss and architectural changes could act as driver for the tissue remodeling process trying to maintain spinal stability in the presence of inflammation. Despite some progress, the nature and mechanisms of new bone formation in axial spondyloarthritis still remain incompletely understood. However, long-term control of inflammation appears critical to avoid progressive disability due to structural damage.

Microtrauma: no longer to be ignored in spondyloarthritis?

PURPOSE OF REVIEW: Novel clinical and animal model data support that biomechanical factors play a role in the onset and progression of spondyloarthritis. Bringing together these insights with the progress made in our understanding of the immunopathogenesis and genetic susceptibility of spondyloarthritis may provide new opportunities for better management. RECENT FINDINGS: Tail suspension prevents arthritis in a tumor necrosis factor overexpression model. A similar approach also reduces new bone formation after acute arthritis in mice. Physical labor is associated with disease severity, including structural disease progression. Sentinel immune cells in the enthesis provide a link between local damage and the development of inflammation. Loss of stability likely triggers tissue remodeling, including the formation of syndesmophytes. Improving muscle strength and control while avoiding excessive strain or overuse should be considered in the approach toward patients. New regulators of tissue turnover and remodeling are emerging including microRNAs. SUMMARY: Local damage may provide a trigger for spondyloarthritis. For structural disease progression loss of stability may be an important factor. Control of inflammation will prevent stability issues and improve the long-term prognosis of disease. Physical therapy will continue to provide benefit for patients in the short and in long-term management of disease.

The effect of forced exercise on knee joints in Dio2(-/-) mice: type II iodothyronine deiodinase-deficient mice are less prone to develop OA-like cartilage damage upon excessive mechanical stress.

OBJECTIVE: To further explore deiodinase iodothyronine type 2 (DIO2) as a therapeutic target in osteoarthritis (OA) by studying the effects of forced mechanical loading on in vivo joint cartilage tissue homeostasis and the modulating effect herein of Dio2 deficiency. METHODS: Wild-type and C57BL/6-Dio2(-/-) -mice were subjected to a forced running regime for 1 h per day for 3 weeks. Severity of OA was assessed by histological scoring for cartilage damage and synovitis. Genome-wide gene expression was determined in knee cartilage by microarray analysis (Illumina MouseWG-6 v2). STRING-db analyses were applied to determine enrichment for specific pathways and to visualise protein-protein interactions. RESULTS: In total, 158 probes representing 147 unique genes showed significantly differential expression with a fold-change ≥1.5 upon forced exercise. Among these are genes known for their association with OA (eg, Mef2c, Egfr, Ctgf, Prg4 and Ctnnb1), supporting the use of forced running as an OA model in mice. Dio2-deficient mice showed significantly less cartilage damage and signs of synovitis. Gene expression response upon exercise between wild-type and knockout mice was significantly different for 29 genes. CONCLUSIONS: Mice subjected to a running regime have significant increased cartilage damage and synovitis scores. Lack of Dio2 protected against cartilage damage in this model and was reflected in a specific gene expression profile, and either mark a favourable effect in the Dio2 knockout (eg, Gnas) or an unfavourable effect in wild-type cartilage homeostasis (eg, Hmbg2 and Calr). These data further support DIO2 activity as a therapeutic target in OA.

Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis.

OBJECTIVES: To identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA. METHODS: The GWAS meta-analysis included approximately 2.5 million imputed HapMap single nucleotide polymorphisms (SNPs). HOA cases and controls defined radiographically and by total hip replacement were selected from the Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF) (654 cases and 4697 controls, combined). Replication of genome-wide significant SNP associations (p ≤5×10(-8)) was examined in five studies (3243 cases and 6891 controls, combined). Functional studies were performed using in vitro models of chondrogenesis and osteogenesis. RESULTS: The A allele of rs788748, located 65 kb upstream of the IGFBP3 gene, was associated with lower HOA odds at the genome-wide significance level in the discovery stage (OR 0.71, p=2×10(-8)). The association replicated in five studies (OR 0.92, p=0.020), but the joint analysis of discovery and replication results was not genome-wide significant (p=1×10(-6)). In separate study populations, the rs788748 A allele was also associated with lower circulating IGFBP3 protein levels (p=4×10(-13)), suggesting that this SNP or a variant in linkage disequilibrium could be an IGFBP3 regulatory variant. Results from functional studies were consistent with association results. Chondrocyte hypertrophy, a deleterious event in OA pathogenesis, was largely prevented upon IGFBP3 knockdown in chondrocytes. Furthermore, IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation. CONCLUSIONS: Results from GWAS and functional studies provided suggestive links between IGFBP3 and HOA.

Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis.

Hip osteoarthritis (HOA) is one of the most disabling and common joint disorders with a large genetic component that is, however, still ill-defined. To date, genome-wide association studies (GWAS) in osteoarthritis (OA) and specifically in HOA have yielded only few loci, which is partly explained by heterogeneity in the OA definition. Therefore, we here focused on radiographically measured joint-space width (JSW), a proxy for cartilage thickness and an important underlying intermediate trait for HOA. In a GWAS of 6,523 individuals on hip-JSW, we identified the G allele of rs12982744 on chromosome 19p13.3 to be associated with a 5% larger JSW (P = 4.8 × 10(-10)). The association was replicated in 4,442 individuals from three United Kingdom cohorts with an overall meta-analysis P value of 1.1 × 10(-11). The SNP was also strongly associated with a 12% reduced risk for HOA (P = 1 × 10(-4)). The SNP is located in the DOT1L gene, which is an evolutionarily conserved histone methyltransferase, recently identified as a potentially dedicated enzyme for Wnt target-gene activation in leukemia. Immunohistochemical staining of the DOT1L protein in mouse limbs supports a role for DOT1L in chondrogenic differentiation and adult articular cartilage. DOT1L is also expressed in OA articular chondrocytes. Silencing of Dot1l inhibited chondrogenesis in vitro. Dot1l knockdown reduces proteoglycan and collagen content, and mineralization during chondrogenesis. In the ATDC5 chondrogenesis model system, DOT1L interacts with TCF and Wnt signaling. These data are a further step to better understand the role of Wnt-signaling during chondrogenesis and cartilage homeostasis. DOT1L may represent a therapeutic target for OA.

Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells.

OBJECTIVES: Spondyloarthritides (SpA) are characterised by both peripheral and axial arthritis. The hallmarks of peripheral SpA are the development of enthesitis, most typically of the Achilles tendon and plantar fascia, and new bone formation. This study was undertaken to unravel the mechanisms leading towards enthesitis and new bone formation in preclinical models of SpA. RESULTS: First, we demonstrated that TNF(ΔARE) mice show typical inflammatory features highly reminiscent of SpA. The first signs of inflammation were found at the entheses. Importantly, enthesitis occurred equally in the presence or absence of mature T and B cells, underscoring the importance of stromal cells. Hind limb unloading in TNF(ΔARE) mice significantly suppressed inflammation of the Achilles tendon compared with weight bearing controls. Erk1/2 signalling plays a crucial role in mechanotransduction-associated inflammation. Furthermore, new bone formation is strongly promoted at entheseal sites by biomechanical stress and correlates with the degree of inflammation. CONCLUSIONS: These findings provide a formal proof of the concept that mechanical strain drives both entheseal inflammation and new bone formation in SpA.

Anti-TNF therapy and malignancy in spondyloarthritis in the Leuven spondyloarthritis biologics cohort (BIOSPAR).

OBJECTIVES: To report the incidence of malignancy in a large single-centre cohort in Belgium of patients with spondyloarthritis (SpA) treated with one or more anti-TNF therapies and to compare the results with the incidence of malignancy in the Belgian population. METHODS: From September 2000 until March 2010, all SpA patients that started treatment with one or more anti-TNF therapies were included in this single-centre prospective longitudinal observational study. The primary outcome of this study was the incidence of malignancy after starting anti-TNF treatment. Incidence rates were compared with the incidence rates of malignancy in Belgium in 2008 for the 45-50 year-old population, as documented by the Belgian Cancer Registry. RESULTS: 231 patients with a mean age of 47.86 y were included for a total of 1020.74 patient years of treatment and 1199.83 patient years follow-up after the start of treatment. In our study population, 6 out of 231 patients (2.6 %) developed a malignancy after the start of anti-TNF treatment. The overall incidence rate of malignancy in our study population is 500.1 per 100000 patient years, indicating a higher incidence compared to the Belgian population. We see a higher incidence rate in females as well in males; standardised incidence ratios are in the same range for both (154.3 for females and 130.6 for males). CONCLUSIONS: We see a tendency towards a higher incidence of malignancy in SpA patients treated with anti-TNF therapy. However, it is not clear whether this increased risk is disease-related or treatment-related.

Proinflammatory Th17 cells are expanded and induced by dendritic cells in spondylarthritis-prone HLA-B27-transgenic rats.

OBJECTIVE: HLA-B27/human ß2-microglobulin-transgenic (B27-transgenic) rats, a model of spondylarthritis (SpA), develop spontaneous colitis and arthritis under conventional conditions. CD4+ T cells are pivotal in the development of inflammation in B27-transgenic rats. This study was undertaken to characterize the phenotype of CD4+ T cells in this model and to determine whether dendritic cells (DCs) induce proinflammatory T cells. METHODS: The phenotype of CD4+ T cells from rat lymph nodes (LNs) draining the sites of inflammation was analyzed by flow cytometry. Immunostaining was used to detect interleukin-17 (IL-17)-producing cells in the rat joints. DCs from B27-transgenic or control rats (transgenic for HLA-B7 or nontransgenic) were cocultured with control CD4+ T cells and stimulated with anti-T cell receptor α/ß. RESULTS: IL-17A- and tumor necrosis factor α (TNFα)-producing CD4+ T cells were expanded in mesenteric and popliteal LNs from B27-transgenic rats. The accumulation of Th17 cells correlated with disease development, in contrast to Th1 or Treg cells. IL-17-positive mononuclear cells were detected in the arthritic joints of B27-transgenic rats but not in the joints of control rats. Finally, in vitro cocultures demonstrated that Th17 cells were preferentially induced and expanded by DCs from B27-transgenic rats, by a process that may involve defective engagement of costimulatory molecules. CONCLUSION: Our findings indicate that expanded CD4+ T cells in B27-transgenic rats exhibit a proinflammatory Th17 phenotype characterized by IL-17A and TNFα production. Furthermore, this population is preferentially induced by DCs from B27-transgenic rats. These data point toward an induction of Th17 cells as a possible pathogenic mechanism in this model of SpA. However, their pathogenic role still needs to be shown.

Innovation in Targeted Intra-articular Therapies for Osteoarthritis.

Osteoarthritis is the most common chronic joint disease characterized by progressive damage to the joints, leading to pain and loss of function. There is currently no cure or disease-modifying therapy for osteoarthritis. Hence, the increasing disease prevalence linked with ageing and obesity represents a substantial socio-economic burden. Intra-articular therapy by injection of drugs into affected joints can optimize local drug bioavailability, while reducing risks of systemic toxicity, a concern in an ageing patient population. In this review, we investigate the current landscape of intra-articular drug therapies for osteoarthritis, including established approaches and those in clinical development. We performed a literature review using PubMed, complemented with a search for clinical trials using the ClinicalTrials.gov repository. Additionally, conference abstracts and presentations were identified and systematic snowballing was applied. Identified drugs were divided into several groups by main mechanism of action, and include drugs that reduce inflammation (anti-inflammatory), drugs aiming to prevent or reverse structural damage (structure modifying), drugs that aim to reduce the pain, and other drugs with a specific target. Most studies have been performed for osteoarthritis of the knee, a joint that is easily accessible for intra-articular treatments. Optimal therapy would provide symptomatic relief, while preventing further damage to the joint. The field of intra-articular drug therapies for osteoarthritis is rapidly evolving with clear challenges identified: definition of relevant outcome measures, optimization of clinical trial set-ups, and dealing with placebo responses. While many uncertainties persist, it appears that the innovation in drug development and improved clinical trial set-up may finally deliver successful therapies for this important disease.

Osteomodulin downregulation is associated with osteoarthritis development.

Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis (OA), and osteomodulin (OMD), a proteoglycan involved in extracellular matrix mineralization, is associated with the sclerotic phenotype. However, the functions of OMD remain poorly understood, specifically in vivo. We used Omd knockout and overexpressing male mice and mutant zebrafish to study its roles in bone and cartilage metabolism and in the development of OA. The expression of Omd is deeply correlated with bone and cartilage microarchitectures affecting the bone volume and the onset of subchondral bone sclerosis and spontaneous cartilage lesions. Mechanistically, OMD binds to RANKL and inhibits osteoclastogenesis, thus controlling the balance of bone remodeling. In conclusion, OMD is a key factor in subchondral bone sclerosis associated with OA. It participates in bone and cartilage homeostasis by acting on the regulation of osteoclastogenesis. Targeting OMD may be a promising new and personalized approach for OA.

Spontaneous arthritis and ankylosis in male DBA/1 mice: further evidence for a role of behavioral factors in "stress-induced arthritis".

BACKGROUND: Ageing male DBA/1 mice spontaneously develop arthritis in the hind paws. We and others have demonstrated that this model shares striking features with human spondyloarthritis, in particular entheseal involvement, progressive ankylosis but also dactylitis. Here, we report on our recent experience with this model highlighting how changes in the animal facility affect the development of the disease. FINDINGS: Ageing male DBA/1 mice from different litters were caged together (6 mice per cage) at the age of 10 weeks. The mice were checked twice a week for clinical signs of arthritis. Disease severity was assessed in further detail post-mortem by scoring for histomorphological characteristics. DBA/1 mice spontaneously develop macroscopically detectable arthritis, presenting as joint swelling or toe stiffness. Standard settings with open cages lead to an almost 100% incidence by the age of 26 weeks. The introduction of larger cages and filter tops reducing exposure to other cages dramatically affected incidence. Other negative factors include excess bedding material reducing the impact of walking and running. Switching back to the original conditions resulted again in a high incidence, further optimized by sensory exposure to female mice. We also showed that the related DBA/2 strain is sensitive to the disease. CONCLUSIONS: Changing environmental factors in the housing conditions of DBA/1 mice severely affects the spontaneous development of arthritis. This points out that the model is very sensitive to external stress and sensory factors that are likely affecting the behavior of the male mice and that the model needs to be optimized in different situations.

Blocking p38 signalling inhibits chondrogenesis in vitro but not ankylosis in a model of ankylosing spondylitis in vivo.

OBJECTIVES: To investigate p38 mitogen activated protein kinase (MAPK) signalling in an in vitro model of bone morphogenetic protein (BMP) and transforming growth factor ß (TGFß)-induced chondrogenesis and in vivo, with specific attention to its potential role in ankylosing enthesitis. METHODS: Human periosteum-derived cells (hPDCs) were cultured in pellets and stimulated with BMP2 or TGFß1 in the presence or absence of a p38 inhibitor SB203580 or proinflammatory cytokines. Chondrogenic differentiation was evaluated using quantitative PCR. Male DBA/1 mice from different litters were caged together at the age of 8 weeks and treated with SB203580 in both a preventive and therapeutic strategy. The mice were evaluated for prospective signs of arthritis and the toe joints were analysed histologically to assess disease severity. RESULTS: p38 inhibition by SB203580 and proinflammatory cytokines downregulated chondrogenic markers in pellet cultures stimulated by BMP2 or TGFß1. In contrast, the in vivo experiments resulted in an increased clinical incidence of arthritis and pathology severity score, reflecting progression towards ankylosis in mice given SB203580. CONCLUSION: Inhibition of p38 inhibited chondrogenic differentiation of progenitor cells, showing that not only the SMAD signalling pathways and also alternative activation of MAPKs including p38 contribute to chondrogenesis. Such an inhibitory effect is not found in an in vivo model of joint ankylosis and spondyloarthritis. Increased incidence and severity of disease in preventive experiments and shifts in disease stages in a therapeutic experimental set-up suggest that specific inhibition of p38 may have deleterious rather than beneficial effects.

Genetic deletion of low-density lipoprotein receptor-related protein 5 increases cartilage degradation in instability-induced osteoarthritis.

OBJECTIVE: The wingless-type MMTV integration site family (WNT) signalling pathway plays an important role in embryonic joint and bone development and has been associated with osteoporosis and osteoarthritis (OA). Loss-of-function mutations in low-density lipoprotein receptor-related protein 5 (LRP5), a WNT co-receptor, result in low bone mass. Lrp5(-)(/)(-) mice also have low bone mass phenotypes. Recently an OA-susceptibility locus containing the LRP5 gene was suggested. We investigated the effects of loss of Lrp5 in joint biology in three different mouse models of OA. METHODS: Total body bone mineral parameters were measured by dual-energy X-ray absorptiometry. Trabecular and cortical bone parameters of tibia and femur were assessed ex vivo by peripheral quantitative CT. Osteoarthritic changes were induced in Lrp5(-)(/)(-) and wild-type C57Bl/6J mice using the surgically induced destabilization of the medial meniscus model and the chemically induced papain and collagenase model. The severity of joint disease was investigated by histological analysis of the knee joints. RESULTS: Bone mineral density and weight were significantly decreased in Lrp5(-)(/)(-) C57Bl/6J mice compared with their wild-type littermates. Surgically induced destabilization of the knee joint resulted in significantly increased cartilage degradation in the medial tibia of Lrp5(-)(/)(-) mice compared with wild-type control mice. In the medial femur, a similar trend was found but did not reach statistical significance. In the papain- and collagenase-induced models, these differences were not observed. Inflammation scores were comparable between wild-type and Lrp5(-)(/)(-) mice. CONCLUSION: These data show that loss of function of Lrp5 increases cartilage degradation in mild instability-induced OA models in mice. Low bone mass density could have contributed to this effect.

Is psoriatic arthritis a result of abnormalities in acquired or innate immunity?

Psoriatic arthritis is a common chronic inflammatory joint disease in which both inflammation and tissue damage contribute to the patient's outcome. Abnormal activation of the innate and the adaptive immune system contributes to the chronic disease process. Novel insights into these immune pathways are further corroborated by genetic evidence. In this review, we compare the current paradigm of psoriasis to mechanisms that likely play a role in psoriatic arthritis and provide an overview of the role of immune mechanisms in the different features of the disease.

Omics and Multi-Omics Analysis for the Early Identification and Improved Outcome of Patients with Psoriatic Arthritis.

The definitive diagnosis and early treatment of many immune-mediated inflammatory diseases (IMIDs) is hindered by variable and overlapping clinical manifestations. Psoriatic arthritis (PsA), which develops in ~30% of people with psoriasis, is a key example. This mixed-pattern IMID is apparent in entheseal and synovial musculoskeletal structures, but a definitive diagnosis often can only be made by clinical experts or when an extensive progressive disease state is apparent. As with other IMIDs, the detection of multimodal molecular biomarkers offers some hope for the early diagnosis of PsA and the initiation of effective management and treatment strategies. However, specific biomarkers are not yet available for PsA. The assessment of new markers by genomic and epigenomic profiling, or the analysis of blood and synovial fluid/tissue samples using proteomics, metabolomics and lipidomics, provides hope that complex molecular biomarker profiles could be developed to diagnose PsA. Importantly, the integration of these markers with high-throughput histology, imaging and standardized clinical assessment data provides an important opportunity to develop molecular profiles that could improve the diagnosis of PsA, predict its occurrence in cohorts of individuals with psoriasis, differentiate PsA from other IMIDs, and improve therapeutic responses. In this review, we consider the technologies that are currently deployed in the EU IMI2 project HIPPOCRATES to define biomarker profiles specific for PsA and discuss the advantages of combining multi-omics data to improve the outcome of PsA patients.

Genome-wide association scan identifies a prostaglandin-endoperoxide synthase 2 variant involved in risk of knee osteoarthritis.

Osteoarthritis (OA), the most prevalent form of arthritis in the elderly, is characterized by the degradation of articular cartilage and has a strong genetic component. Our aim was to identify genetic variants involved in risk of knee OA in women. A pooled genome-wide association scan with the Illumina550 Duo array was performed in 255 controls and 387 cases. Twenty-eight variants with p < 1 x 10(-5) were estimated to have probabilities of being false positives