Background: Osteoarthritis is a chronic musculoskeletal disease characterized by age-related gradual thinning and a high risk in females. Recent studies have shown that DNA methylation plays important roles in osteoarthritis. However, the genome-wide pattern of methylation in enhancers in osteoarthritis remains unclear. Methods: To explore the function of enhancers in osteoarthritis, we quantified CpG methylation in human enhancers based on a public dataset that included methylation profiles of 470,870 CpG probes in 108 samples from patients with hip and knee osteoarthritis and hip tissues from healthy individuals. Combining various bioinformatics analysis tools, we systematically analyzed aberrant DNA methylation of the enhancers throughout the genome in knee osteoarthritis and hip osteoarthritis. Results: We identified 16,816 differentially methylated CpGs, and nearly half (8111) of them were from enhancers, suggesting major DNA methylation changes in both types of osteoarthritis in the enhancer regions. A detailed analysis of hip osteoarthritis identified 2426 differentially methylated CpGs in enhancers between male and female patients, and 84.5% of them were hypomethylated in female patients and enriched in phenotypes related to hip osteoarthritis in females. Next, we explored the enhancer methylation dynamics among patients with knee osteoarthritis and identified 280 differentially methylated enhancer CpGs that were enriched in the human phenotypes and disease ontologies related to osteoarthritis. Finally, a comparison of enhancer methylation between knee osteoarthritis and hip osteoarthritis revealed organ source-dependent differences in enhancer methylation. Conclusion: Our findings indicate that aberrant methylation of enhancers is related to osteoarthritis phenotypes, and a comprehensive atlas of enhancer methylation is useful for further analysis of the epigenetic regulation of osteoarthritis and the development of clinical drugs for treatment of osteoarthritis.

Among osteoarthritis (OA) subtypes, hand osteoarthritis (HOA) is the fastest-growing by estimated annual percentage change in age-standardized rates and percentage change in case numbers. Yet its burden in adults aged ≥55 years, who are disproportionately affected, has not been systematically quantified. Using Global Burden of Disease 2021 data, we assessed the global burden of HOA in this age group. Trends were analyzed using estimated annual percentage change and percentage change, and future projections were made using an autoregressive integrated moving average model. From 1990 to 2021, incident cases, prevalent cases, and years lived with disability (YLDs) in this age group increased by 3.13 million, 95.32 million, and 2.99 million, accounting for 51.40%, 80.80%, and 79.95% of total increases in the general population, respectively. In 2021, there were 5.13 million incident cases, 154.68 million prevalent cases, and 4.86 million YLDs, representing 49.52%, 79.61%, and 78.77% of the global burden, respectively, with corresponding age-standardized rates of 2.89, 4.71, and 4.66 times those in the general population. China, India, the United States, Japan, Russia, and Brazil together accounted for over 54% of incident cases, prevalent cases, and YLDs. By 2050, incident cases, prevalent cases, and YLDs are projected to reach 8.99 million, 292 million, and 8.96 million, respectively, with corresponding age-standardized rates of 2.57, 5.13, and 5.01 times those in the general population. The growth in HOA burden in this age group over the past 3 decades and through 2050 exceeds that of other osteoarthritis subtypes. The burden of HOA in adults aged ≥55 years is disproportionately high and is increasing faster than any other osteoarthritis subtype, with 6 countries (China, India, the United States, Japan, Russia, and Brazil) bearing the heaviest absolute burden. Thus, HOA in this age group has emerged as a global challenge demanding sufficient attention.