Extraction of bone contours from radiographs plays an important role in disease diagnosis, preoperative planning, and treatment analysis. We present a fully automatic method to accurately segment the proximal femur in anteroposterior pelvic radiographs. A number of candidate positions are produced by a global search with a detector. Each is then refined using a statistical shape model together with local detectors for each model point. Both global and local models use Random Forest regression to vote for the optimal positions, leading to robust and accurate results. The performance of the system is evaluated using a set of 839 images of mixed quality. We show that the local search significantly outperforms a range of alternative matching techniques, and that the fully automated system is able to achieve a mean point-to-curve error of less than 0.9 mm for 99% of all 839 images. To the best of our knowledge, this is the most accurate automatic method for segmenting the proximal femur in radiographs yet reported.

SummaryBackgroundOsteoarthritis 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.MethodsWe 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.FindingsWe 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.InterpretationOur findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.FundingarcOGEN was funded by a special purpose grant from Arthritis Research UK.

Objective-Oxidative stress is proposed as an important factor in osteoarthritis (OA). We therefore investigated the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA.Methods-SOD expression was determined by real-time polymerase chain reaction and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulfite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX™ and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression.Results-All three SOD were abundantly expressed in human cartilage but were markedly down-regulated in end-stage OA cartilage, especially SOD2. In the Dunkin Hartley guinea pig spontaneous OA model SOD2 expression was decreased in the medial tibial chondyle cartilage prior to, and following, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes gave an increase in ROS but a decrease in collagenase expression.Conclusion-This is the first comprehensive expression profile of all SOD genes in cartilage and importantly, using an animal model, we show that a reduction in SOD2 is associated with the earliest stages of OA. We found that a decrease in SOD2 associates with an increase in ROS and but a reduction of collagenase gene expression, demonstrating the complexities of ROS function.