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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 × 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., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The objective was to assess the effect of doxycycline treatment on a magnetic resonance imaging (MRI) biomarker of cartilage volume loss, and on matrix metalloproteinase (MMP) activity in a guinea pig osteoarthritis model. Guinea pigs (9 months old) were dosed with vehicle or doxycycline, 0.6, 3.0 mg/kg/day for 66 days. Fat-suppressed 3D gradient-echo MRI of the left knee was acquired pre- and post dosing. Change in medial tibial plateau (MTP) cartilage volume (MT.VC) was determined using image analysis. At termination, MTP cartilage was removed from knees and proteolytic MMP activity determined using a fluorescent peptide substrate assay. Vehicle-treated animals lost 20.5% (95% CI mean 25.6-15.1) MT.VC. The doxycycline (0.6 mg/kg/day) group lost 8.6% (P < 0.05, 95% CI 20.6 to -5.3) whilst the 3.0 mg/kg/day group lost 10.0% (P < 0.05, 95% CI 13.9-6.0%). Endogenous levels of active MMPs were below limits of detection in all samples. However, doxycycline treatment ablated amino phenyl mercuric acid activated MMP-13 and MMP-8 levels, reduced MMP-9 levels by 65% and MMP-1 levels by 24%. Doxycycline treatment resulted in partial protection from MT.VC loss and was associated with complete reduction in MMP-13 and MMP-8, and partial reduction in MMP-9 activity. These data imply a role of MMPs in cartilage degeneration but incomplete protection suggests that additional doxycycline insensitive mechanisms are important in this model. The protective effect of doxycycline correlates with the clinical finding of lessened joint space narrowing, strengthens the utility of this animal model in identifying disease-modifying osteoarthritic drugs and supports the use of MRI biomarkers of cartilage loss.

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

Animal models have been used for a number of decades to study arthritis and have contributed greatly to unravelling mechanisms of pathogenesis and validating new targets for treatment. All animal models have sets of limitations and over the years there has been natural refinement of existing models as well as creation of new ones. The success of genetic modification in mice has fuelled an exponential increase in the use of murine models for arthritis research and has significantly increased our understanding of disease processes. This review focuses on those rodent models of RA and OA that have current utility and are widely used by the research community. We highlight the subtle but important differences in existing models by positioning them on a pathogenesis map whereby model selection is determined by the specific aspect of disease to be studied. We discuss the evolving challenges in in vivo arthritis studies and our perceived gaps for future new model development. The document includes technical and cost implications of performing the described models, and the ethical considerations of such approaches. [ABSTRACT FROM AUTHOR]

Objectives: To determine cross-sectionally the influence of risk factors on chronic pain following total joint replacement (TJR) of the knee (TKR) or the hip (THR). Methods: Eight hundred sixty post-TKR and 928 post-THR patients were studied. Western Ontario and McMaster Osteoarthritis Index pain scores taken on average 3.2 years postsurgery were correlated to preoperative radiographic severity measured by Kellgren-Lawrence grade (K/L) grade for the knee, Croft grade, and minimum joint space width (minJSW) for the hip and presence of comorbidities. Results: Known risk factors were able to explain less than 20% of the variance in pain scores post-TJR. The presence of chronic widespread pain determined a higher risk of high pain in both TKR cases (odds ratio (OR) = 3.15 95%CI 1.86-5.30) and THR cases (OR = 5.02 95%CI 2.76-9.14). Other risk factors common to both TKR and THR pain postsurgery were the presence of depression, higher body mass index, younger age, and female gender. Interestingly, low radiographic grade at the index joint presurgery (defined as tibiofemoral K/L <3 for the knee and minJSW >2 mm for the hip) resulted in a significantly increased risk of high pain post-TJR (OR = 1.56; 95%CI 1.04-2.36). Conclusions: The risk factors contributing to chronic pain post-TJR remain mostly unknown. Individuals with lower preoperative radiographic OA severity undergoing TJR are more likely to experience high pain post-TJR. [Copyright &y& Elsevier]

Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR) = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the metaanalysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r2 = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r2<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals. [ABSTRACT FROM AUTHOR]

The article examines the differences in risk factors influencing total hip replacement (THR) and total knee replacement (TKR) according to the presence and absence of multiple interphalangeal nodes in patients with large joint osteoarthritis (OA). The results revealed that age, sex and body mass index (BMI) are highly associated with total joint replacement in nodal OA cases than non-nodal OA cases. It was also found out that GDF5 polymorphism was associated with THR in nodal OA cases and increased height was a risk factor for THR in non-nodal OA cases.

Magnetic resonance imaging (MRI) is emerging as the method of choice for measuring cartilage loss in osteoarthritis (OA), but current methods of analysis are imperfect for therapeutic clinical trials. In this paper, we present and evaluate, in two multicenter multivendor studies, a new method for anatomically corresponded regional analysis of cartilage (ACRAC) that allows analysis of knee cartilage morphology in anatomically corresponding focal regions defined on the bone surface. In our first study, 3-D knee MR Images were obtained from 19 asymptomatic female volunteers, followed by segmentations of the bone and cartilage. Minimum description length (MDL) statistical shape models (SSMs) were constructed from the segmented bone surfaces, providing mean bone shapes and a dense set of anatomically corresponding positions on each individual bone, the accuracy of which were measured using repeat images from a subset of the volunteers. Cartilage thicknesses were measured at these locations along 3-D normals to the bone surfaces, yielding corresponded cartilage thickness maps. Functional subregions of the joint were defined on the mean bone shapes, and propagated, using the correspondences, to each individual. ACRAC improved reproducibility, particularly in the central, load bearing subregions of the joint, compared with measures of volume obtained directly from the segmented cartilage surfaces. In our second study, MR Images were obtained from 31 female patient-volunteers with knee OA at baseline and six months. We obtained manual segmentations of the cartilage, and automatic segmentations of the bone using active appearance models (AAMs) built from the bone SSMs of the first study. ACRAC enabled the detection of significant thickness loss in the central, load-bearing regions of the whole femur (-5.57% p = 0.01, annualized) and the medial condyle (-13.08%, p = 0.024 Bonferroni corrected, annualized). We conclude that statistical shape modelling of bone surfaces defines correspondences invariant to individual joint size or shape, providing focal measures of cartilage with improved reproducibility compared to whole compartment measures. It permits the identification of anatomically equivalent regions, and provides the ability to identify the main load-bearing regions of the joint, based on the imputed premorbid state. The method permitted detection of tiny morphological change in cartilage thickness over six months in a small study, and may be useful for OA disease analysis and treatment monitoring. [ABSTRACT FROM AUTHOR]

The article presents the study which examines the association of nonspherical femoral head shape or pistol grip deformity and neck shaft angle as risk factors of hip osteoarthritis (OA). It focuses on the findings which indicate the increased prevalence of pistol grip deformity and an abnormally low neck shaft angle in unaffected hips are risk factors for development of hip OA. However, both a nonspherical head shape and an increase in neck shaft angle may occur as a consequence of OA.

Objective: Recent findings suggest that β-adrenergic blockers have antinociceptive properties. The aim of this study was to compare levels of large-joint pain between those taking adrenergic blockers and those taking other antihypertensive medications.Methods: Data from the Genetics of Osteoarthritis and Lifestyle (GOAL) study, a secondary-care cohort of osteoarthritis (OA) patients, were used. Joint pain was assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores in 873 individuals with symptomatic hip and/or knee OA and hypertension, who were taking ≥1 prescription antihypertensive medications. The association between adrenergic blocker prescription and at least moderate joint pain (WOMAC score <75) and use of prescription analgesics was examined using binary logistic regression. Analyses were adjusted for age, sex, body mass index, knee or hip OA, history of joint replacement (at other joints), anxiety, and depression.Results: The use of β-adrenergic blockers was associated with lower WOMAC pain scores and with a lower prevalence of joint pain after adjustment for demographic variables and comorbidity (adjusted odds ratio [ORadj ] for pain 0.68 [95% confidence interval (95% CI) 0.51, 0.92]; P < 0.011). No associations with pain were observed with use of alpha-blockers (ORadj for pain 0.94 [95% CI 0.55, 1.58]) or with any other class of antihypertensive medications. Prescription of beta-blockers was also associated negatively with opioid use (ORadj for opioids 0.73 [95% CI 0.54, 0.98]; P < 0.037) and with the use of prescription analgesics in general (ORadj for analgesics 0.74 [95% CI 0.56, 0.94]; P < 0.032).Conclusion: The use of beta-blockers is associated with less joint pain and a lower use of opioids and other analgesics in individuals with symptomatic large-joint OA. This observation needs to be confirmed by other studies. [ABSTRACT FROM AUTHOR]