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 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.

There is public concern over the long term systemic health effects of metal released from hip replacement prostheses that use large-diameter metal-on-metal bearings. However, to date there has been no systematic study to determine which organs may be at risk, or the magnitude of any effect. We undertook a detailed cross-sectional health screen at a mean of 8 years after surgery in 35 asymptomatic patients who had previously received a metal-on-metal hip resurfacing (MoMHR) versus 35 individually age and sex matched asymptomatic patients who had received a conventional hip replacement. Total body bone mineral density was 5% higher (mean difference 0.05 g/cm², P = 0.02) and bone turnover was 14% lower (TRAP 5b, mean difference −0.56IU/L, P = 0.006; osteocalcin, mean difference −3.08 ng/mL, P = 0.03) in the hip resurfacing versus conventional hip replacement group. Cardiac ejection fraction was 7% lower (mean absolute difference −5%, P = 0.04) and left ventricular end-diastolic diameter was 6% larger (mean difference 2.7 mm, P = 0.007) in the hip resurfacing group versus those patients who received a conventional hip replacement. The urinary fractional excretion of metal was low (cobalt 5%, chromium 1.5%) in patients with MoMHR, but creatinine clearance was normal. Diuretic prescription was associated with a 40% increase in the fractional excretion of chromium (mean difference 0.5%, P = 0.03). There was no evidence of difference in neuropsychological, renal tubular, hepatic or endocrine function between groups (P>0.05). Our findings of differences in bone and cardiac function between patient groups suggest that chronic exposure to low elevated metal concentrations in patients with well-functioning MoMHR prostheses may have systemic effects. Long-term epidemiological studies in patients with well-functioning metal on metal hip prostheses should include musculoskeletal and cardiac endpoints to quantitate the risk of clinical disease.

Objectives To examine the extent of brain abnormality in patients with coeliac disease referred for neurological opinion and evaluate MR imaging sequences as biomarkers for neurological dysfunction, given the lack of readily available serological markers of neurological disease in this cohort. Methods Retrospective examination of a consecutive cohort of patients (n=33, mean age=44±13 years (range 19–64)) with biopsy proven coeliac disease referred for neurological opinion. Patients were divided into subgroups based on their primary neurological complaint (balance disturbance, headache and sensory loss). 3T MR was used to evaluate differences in brain grey matter density, cerebellar volume, cerebellar neurochemistry and white matter abnormalities (WMAs) between subjects and controls. Results Cerebellar volume was significantly less in the patient group than in controls (6.9±0.7% vs 7.4±0.9% of total intracranial volume, p<0.05). Significantly less grey matter density was found in multiple brain regions, both above and below the tentorium cerebelli, than in controls (p<0.05). 12 (36%) patients demonstrated WMAs unexpected for the patient's age, with the highest incidence occurring in the headache subgroup. This subgroup averaged almost twice the number of WMAs per MR imaging than the subgroup with balance disturbance and six times more than the subgroup with sensory loss. Conclusion Patients with established coeliac disease referred for neurological opinion show significant brain abnormality on MR imaging. MR imaging may provide valuable biomarkers of disease in this patient cohort.

BACKGROUND AND PURPOSE: Hip prostheses that use a metal-on-metal articulation expose the brain to elevated metal concentrations that, in acute excess due to prosthesis malfunction, is associated with neurologic damage, including visual and hearing loss and motor deficits. Here, we examined whether chronic exposure to lower elevated metal levels, typical of well-functioning prostheses, also affects brain structure and function. MATERIALS AND METHODS: We compared brain volumes, metal deposition, and gray matter attenuation by MR imaging and clinical neurologic function in patients 8 years after receiving a metal-on-metal hip resurfacing versus a matched group of patients with the same duration exposure to a conventional hip prosthesis. RESULTS: Twenty-nine patients (25 men; mean, age 59 ± 7 years) after metal-on-metal hip resurfacing and 29 patients (25 men; 59 ± 8 years) after total hip arthroplasty were compared. Whole blood cobalt and chromium concentrations were 5–10 times higher in the metal-on-metal hip resurfacing group (P < .0001). Occipital cortex gray matter attenuation tended to be lower (P < .005 uncorrected, P > .05 corrected), and the optic chiasm area tended to be lower (mean difference, −2.7 mm²; P = .076) in the metal-on-metal hip resurfacing group. Subgroup analyses in 34 patients (17 per group), after exclusion of primary ocular pathology, showed the same trend in gray matter attenuation in the occipital cortex and basal ganglia and a smaller optic chiasm in the metal-on-metal hip resurfacing group (mean difference, −3.9 mm²; P = .048). No other structural or functional differences were found between the groups. CONCLUSIONS: Chronic exposure to metal-on-metal hip resurfacing is associated with subtle structural change in the visual pathways and the basal ganglia in asymptomatic patients.

The mechanisms of cerebellar degeneration attributed to prolonged and excessive alcohol intake remain unclear. Additional or even alternative causes of cerebellar degeneration are often overlooked in suspected cases of alcohol-related ataxia. The objectives of this study were two fold: (1) to investigate the prevalence of gluten-related serological markers in patients with alcohol-related ataxia and; (2) to compare the pattern of brain involvement on magnetic resonance imaging between patients with alcohol and gluten ataxias. Patients diagnosed with alcohol and gluten ataxias were identified from a retrospective review of patients attending a tertiary clinic. HLA genotype and serological markers of gluten-related disorders were recorded. Cerebellar volumetry, MR spectroscopy and voxel-based morphometric analyses were performed on patients and compared with matched control data. Of 904 registered patients, 104 had alcohol ataxia and 159 had gluten ataxia. 61% of the alcohol ataxia group and 70% of the gluten ataxia group had HLA DQ2/DQ8 genotype compared to 30% in healthy local blood donors. 44% of patients with alcohol ataxia had antigliadin antibodies compared to 12% in the healthy local population and 10% in patients with genetically confirmed ataxias. None of the patients with alcohol ataxia and antigliadin antibodies had celiac disease compared to 40% in patients with gluten ataxia. The pattern of structural brain abnormality in patients with alcohol ataxia who had antigliadin antibodies differed from gluten ataxia and was identical to that of alcohol ataxia. Alcohol related cerebellar degeneration may, in genetically susceptible individuals, induce sensitization to gluten. Such sensitization may result from a primary cerebellar insult, but a more systemic effect is also possible. The duration and amount of exposure to alcohol may not be the only factors responsible for the cerebellar insult.