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.
Aims The current global pandemic due to COVID-19 is generating significant burden on the health service in the UK. On 23 March 2020, the UK government issued requirements for a national lockdown. The aim of this multicentre study is to gain a greater understanding of the impact lockdown has had on the rates, mechanisms and types of injuries together with their management across a regional trauma service. Methods Data was collected from an adult major trauma centre, paediatric major trauma centre, district general hospital, and a regional hand trauma unit. Data collection included patient demographics, injury mechanism, injury type and treatment required. Time periods studied corresponded with the two weeks leading up to lockdown in the UK, two weeks during lockdown, and the same two-week period in 2019. Results There was a 55.7% (12,935 vs 5,733) reduction in total accident and emergency (A&E) attendances with a 53.7% (354 vs 164) reduction in trauma admissions during lockdown compared to 2019. The number of patients with fragility fractures requiring admission remained constant (32 patients in 2019 vs 31 patients during lockdown; p > 0.05). Road traffic collisions (57.1%, n = 8) were the commonest cause of major trauma admissions during lockdown. There was a significant increase in DIY related-hand injuries (26% (n = 13)) lockdown vs 8% (n = 11 in 2019, p = 0.006) during lockdown, which resulted in an increase in nerve injuries (12% (n = 6 in lockdown) vs 2.5% (n = 3 in 2019, p = 0.015) and hand infections (24% (n = 12) in lockdown vs 6.2% (n = 8) in 2019, p = 0.002). Conclusion The national lockdown has dramatically reduced orthopaedic trauma admissions. The incidence of fragility fractures requiring surgery has not changed. Appropriate provision in theatres should remain in place to ensure these patients can be managed as a surgical priority. DIY-related hand injuries have increased which has led to an increased in nerve injuries requiring intervention.
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.
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