From mechanism to medicine: The progress and potential of epigenetics in osteoarthritis.

Osteoarthritis (OA) is a chronic, degenerative disease of the articular joints. The disease presents an enormous clinical and economic burden globally, due in part to the lack of disease modifying therapies. For over a decade, OA researchers have been working to determine epigenetic mechanisms underlying the disease to better understand pathology, identify biomarkers of progression, and pinpoint novel targets for therapeutic intervention. This article presents a summary of the 3rd International Workshop on the Epigenetics of Osteoarthritis held in Toronto, Ontario, Canada, in September 2024. The purpose of this meeting was to gather the international community to discuss the status of OA epigenetic research and share expertise on innovative techniques for future. Since the two previous meetings, there has been increasing adoption of advanced single-cell and spatial sequencing technologies and bioinfomatic analyses. Furthermore, investigations of multiple joint tissues has highlighted the shifting paradigm from OA as a cartilage centric disease to the consideration of all joint tissues. The workshop provided a unique opportunity for early-career researchers to expand their network, and for all participants to discuss new or improved approaches to advance the field, including international consortia and data sharing. The highlights and outcomes from this OA epigenetics workshop are described in this report

From mechanism to medicine: The progress and potential of epigenetics in osteoarthritis

\ua9 2025 The Authors. Objective: Osteoarthritis (OA) is a chronic, degenerative disease of the articular joints. The disease presents an enormous clinical and economic burden globally, due in part to the lack of disease modifying therapies. For over a decade, OA researchers have been working to determine epigenetic mechanisms underlying the disease to better understand pathology, identify biomarkers of progression, and pinpoint novel targets for therapeutic intervention. Design: This article presents a summary of the 3rd International Workshop on the Epigenetics of Osteoarthritis held in Toronto, Ontario, Canada, in September 2024. The purpose of this meeting was to gather the international community to discuss the status of OA epigenetic research and share expertise on innovative techniques for future. Results: Since the two previous meetings, there has been increasing adoption of advanced single-cell and spatial sequencing technologies and bioinfomatic analyses. Furthermore, investigations of multiple joint tissues has highlighted the shifting paradigm from OA as a cartilage centric disease to the consideration of all joint tissues. Conclusions: The workshop provided a unique opportunity for early-career researchers to expand their network, and for all participants to discuss new or improved approaches to advance the field, including international consortia and data sharing. The highlights and outcomes from this OA epigenetics workshop are described in this report

Annotating Transcriptional Effects of Genetic Variants in Disease-Relevant Tissue: Transcriptome-Wide Allelic Imbalance in Osteoarthritic Cartilage

Objective. Multiple single-nucleotide polymorphisms (SNPs) conferring susceptibility to osteoarthritis (OA) mark imbalanced expression of positional genes in articular cartilage, reflected by unequally expressed alleles among heterozygotes (allelic imbalance [AI]). We undertook this study to explore the articular cartilage transcriptome from OA patients for AI events to identify putative disease-driving genetic variation. Methods. AI was assessed in 42 preserved and 5 lesioned OA cartilage samples (from the Research Arthritis and Articular Cartilage study) for which RNA sequencing data were available. The count fraction of the alternative alleles among the alternative and reference alleles together (φ) was determined for heterozygous individuals. A meta-analysis was performed to generate a meta-φ and P value for each SNP with a false discovery rate (FDR) correction for multiple comparisons. To further validate AI events, we explored them as a function of multiple additional OA features. Results. We observed a total of 2,070 SNPs that consistently marked AI of 1,031 unique genes in articular cartilage. Of these genes, 49 were found to be significantly differentially expressed (fold change 2, FDR <0.05) between preserved and paired lesioned cartilage, and 18 had previously been reported to confer susceptibility to OA and/or related phenotypes. Moreover, we identified notable highly significant AI SNPs in the CRLF1, WWP2, and RPS3 genes that were related to multiple OA features. Conclusion. We present a framework and resulting data set for researchers in the OA research field to probe for disease-relevant genetic variation that affects gene expression in pivotal disease-affected tissue. This likely includes putative novel compelling OA risk genes such as CRLF1, WWP2, and RPS3

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets

Evolution and advancements in genomics and epigenomics in OA research: How far we have come

\ua9 2024 Osteoarthritis Research Society InternationalObjective: Osteoarthritis (OA) is the most prevalent musculoskeletal disease affecting articulating joint tissues, resulting in local and systemic changes that contribute to increased pain and reduced function. Diverse technological advancements have culminated in the advent of high throughput “omic” technologies, enabling identification of comprehensive changes in molecular mediators associated with the disease. Amongst these technologies, genomics and epigenomics – including methylomics and miRNomics, have emerged as important tools to aid our biological understanding of disease. Design: In this narrative review, we selected articles discussing advancements and applications of these technologies to OA biology and pathology. We discuss how genomics, deoxyribonucleic acid (DNA) methylomics, and miRNomics have uncovered disease-related molecular markers in the local and systemic tissues or fluids of OA patients. Results: Genomics investigations into the genetic links of OA, including using genome-wide association studies, have evolved to identify 100+ genetic susceptibility markers of OA. Epigenomic investigations of gene methylation status have identified the importance of methylation to OA-related catabolic gene expression. Furthermore, miRNomic studies have identified key microRNA signatures in various tissues and fluids related to OA disease. Conclusions: Sharing of standardized, well-annotated omic datasets in curated repositories will be key to enhancing statistical power to detect smaller and targetable changes in the biological signatures underlying OA pathogenesis. Additionally, continued technological developments and analysis methods, including using computational molecular and regulatory networks, are likely to facilitate improved detection of disease-relevant targets, in-turn, supporting precision medicine approaches and new treatment strategies for OA

Evolution and advancements in genomics and epigenomics in OA research: How far we have come.

Osteoarthritis (OA) is the most prevalent musculoskeletal disease affecting articulating joint tissues, resulting in local and systemic changes that contribute to increased pain and reduced function. Diverse technological advancements have culminated in the advent of high throughput "omic" technologies, enabling identification of comprehensive changes in molecular mediators associated with the disease. Amongst these technologies, genomics and epigenomics - including methylomics and miRNomics, have emerged as important tools to aid our biological understanding of disease. In this narrative review, we selected articles discussing advancements and applications of these technologies to OA biology and pathology. We discuss how genomics, deoxyribonucleic acid (DNA) methylomics, and miRNomics have uncovered disease-related molecular markers in the local and systemic tissues or fluids of OA patients. Genomics investigations into the genetic links of OA, including using genome-wide association studies, have evolved to identify 100+ genetic susceptibility markers of OA. Epigenomic investigations of gene methylation status have identified the importance of methylation to OA-related catabolic gene expression. Furthermore, miRNomic studies have identified key microRNA signatures in various tissues and fluids related to OA disease. Sharing of standardized, well-annotated omic datasets in curated repositories will be key to enhancing statistical power to detect smaller and targetable changes in the biological signatures underlying OA pathogenesis. Additionally, continued technological developments and analysis methods, including using computational molecular and regulatory networks, are likely to facilitate improved detection of disease-relevant targets, in-turn, supporting precision medicine approaches and new treatment strategies for OA

Integrative epigenomics, transcriptomics and proteomics of patient chondrocytes reveal genes and pathways involved in osteoarthritis.

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

Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis

Objectives To investigate how the genetic susceptibility gene DIO2 confers risk to osteoarthritis (OA) onset in humans and to explore whether counteracting the deleterious effect could contribute to novel therapeutic approaches. Methods Epigenetically regulated expression of DIO2 was explored by assessing methylation of positional CpG-dinucleotides and the respective DIO2 expression in OA-affected and macroscopically preserved articular cartilage from end-stage OA patients. In a human in vitro chondrogenesis model, we measured the effects when thyroid signalling during culturing was either enhanced (excess T3 or lentiviral induced DIO2 overexpression) or decreased (iopanoic acid). Results OA-related changes in methylation at a specific CpG dinucleotide upstream of DIO2 caused significant upregulation of its expression (beta=4.96; p=0.0016). This effect was enhanced and appeared driven specifically by DIO2 rs225014 risk allele carriers (beta=5.58, p=0.0006). During in vitro chondrogenesis, DIO2 overexpression resulted in a significant reduced capacity of chondrocytes to deposit extracellular matrix (ECM) components, concurrent with significant induction of ECM degrading enzymes (ADAMTS5, MMP13) and markers of mineralisation (ALPL, COL1A1). Given their concurrent and significant upregulation of expression, this process is likely mediated via HIF-2 alpha/RUNX2 signalling. In contrast, we showed that inhibiting deiodinases during in vitro chondrogenesis contributed to prolonged cartilage homeostasis as reflected by significant increased deposition of ECM components and attenuated upregulation of matrix degrading enzymes. Conclusions Our findings show how genetic variation at DIO2 could confer risk to OA and raised the possibility that counteracting thyroid signalling may be a novel therapeutic approach

Mapping 5-Hydroxymethylcytosine (5hmC) Modifications in Skeletal Tissues Using High-Throughput Sequencing

International audienc