Sexually dimorphic metabolic effects of a high fat diet on knee osteoarthritis in mice.

Background: Women have a higher risk of developing osteoarthritis (OA) than men, including with obesity. To better understand this disparity, we investigated sex differences in metabolic and inflammatory factors associated with OA using a diet-induced mouse model of obesity. We hypothesized that 20 weeks of high-fat diet (HFD) would induce sexually dimorphic changes in both systemic and local risk factors of knee OA.

OA susceptibility in mice is partially mediated by the gut microbiome, is transferrable via microbiome transplantation and is associated with immunophenotype changes.

Objectives: The Murphy Roths Large (MRL)/MpJ 'superhealer' mouse strain is protected from post-traumatic osteoarthritis (OA), although no studies have evaluated the microbiome in the context of this protection. This study characterised microbiome differences between MRL and wild-type mice, evaluated microbiome transplantation and OA and investigated microbiome-associated immunophenotypes.

Methods: Cecal material from mixed sex C57BL6/J (B6) or female MRL/MpJ (MRL) was transplanted into B6 and MRL mice, then OA was induced by disruption of the medial meniscus surgery (DMM).

Murine cartilage microbial DNA deposition occurs rapidly following the introduction of a gut microbiome and changes with obesity, aging, and knee osteoarthritis.

Cartilage microbial DNA patterns have been recently characterized in osteoarthritis (OA). The objectives of this study were to evaluate the gut origins of cartilage microbial DNA, to characterize cartilage microbial changes with age, obesity, and OA in mice, and correlate these to gut microbiome changes. We used 16S rRNA sequencing performed longitudinally on articular knee cartilage from germ-free (GF) mice following oral microbiome inoculation and cartilage and cecal samples from young and old wild-type mice with/without high-fat diet-induced obesity (HFD) and with/without OA induced by destabilization of the medial meniscus (DMM) to evaluate gut and cartilage microbiota.

Sex-Linked Discrepancies in C57BL6/J Mouse Osteoarthritis are Associated With the Gut Microbiome and are Transferrable by Microbiome Transplantation.

Objective: Females have reduced osteoarthritis (OA) in surgical models. The objective of the current study was to evaluate a sex-linked gut microbiome in the pathogenesis of OA.

Methods: We induced OA via destabilization of the medial meniscus surgery in adult male and female C57BL6/J mice with and without opposite-sex microbiome transplantation.

Peripheral Blood DNA Methylation-Based Machine Learning Models for Prediction of Knee Osteoarthritis Progression: Biologic Specimens and Data From the Osteoarthritis Initiative and Johnston County Osteoarthritis Project.

Objective: The lack of accurate biomarkers to predict knee osteoarthritis (OA) progression is a key unmet need in OA clinical research. The objective of this study was to develop baseline peripheral blood epigenetic biomarker models to predict knee OA progression.

Methods: Genome-wide buffy coat DNA methylation patterns from 554 individuals from the Osteoarthritis Biomarkers Consortium (OABC) were determined using Illumina Infinium MethylationEPIC 850K arrays.

A Pilot Analysis of Genome-Wide DNA Methylation Patterns in Mouse Cartilage Reveals Overlapping Epigenetic Signatures of Aging and Osteoarthritis.

Objective: Cartilage epigenetic changes are strongly associated with human osteoarthritis (OA). However, the influence of individual environmental OA risk factors on these epigenetic patterns has not been determined; herein we characterize cartilage DNA methylation patterns associated with aging and OA in a mouse model.

Methods: Murine knee cartilage DNA was extracted from healthy young (16-week, n = 6), old (82-week, n = 6), and young 4-week post-destabilization of the medial meniscus (DMM) OA (n = 6) C57BL6/J mice.

The Microbiome in Osteoarthritis: a Narrative Review of Recent Human and Animal Model Literature.

Purpose Of The Review: The microbiome has recently emerged as a powerful contributor to health and illness in chronic, systemic disorders. Furthermore, new microbiome niches beyond traditional gut locations are frequently being described. Over the past 5 years, numerous pivotal studies have demonstrated associations between changes in various microbiome niches and the development of osteoarthritis (OA).

DNA methylation and noncoding RNA in OA: Recent findings and methodological advances.

Introduction: Osteoarthritis (OA) is a chronic musculoskeletal disease characterized by progressive loss of joint function. Historically, it has been characterized as a disease caused by mechanical trauma, so-called 'wear and tear'. Over the past two decades, it has come to be understood as a complex systemic disorder involving gene-environmental interactions.

Ear wound healing in MRL/MpJ mice is associated with gut microbiome composition and is transferable to non-healer mice via microbiome transplantation.

Objective: Adult elastic cartilage has limited repair capacity. MRL/MpJ (MRL) mice, by contrast, are capable of spontaneously healing ear punctures. This study was undertaken to characterize microbiome differences between healer and non-healer mice and to evaluate whether this healing phenotype can be transferred via gut microbiome transplantation.

COVID-19: A review of therapeutic strategies and vaccine candidates.

The world is engulfed by one of the most widespread and significant public health crises in decades as COVID-19 has become among the leading causes of death internationally. The novel SARS-CoV-2 coronavirus which causes COVID-19 has unified the scientific community in search of therapeutic and preventative solutions. The top priorities at the moment are twofold: first, to repurpose already-approved pharmacologic agents or develop novel therapies to reduce the morbidity and mortality associated with the ever-spreading virus.

The Development of Epigenetics in the Study of Disease Pathogenesis.

The study of epigenetics has its roots in the study of organism change over time and response to environmental change, although over the past several decades the definition has been formalized to include heritable alterations in gene expression that are not a result of alterations in underlying DNA sequence. In this chapter, we discuss first the history and milestones in the 100+ years of epigenetic study, including early discoveries of DNA methylation, histone posttranslational modification, and noncoding RNA. We then discuss how epigenetics has changed the way that we think of both health and disease, offering as examples studies examining the epigenetic contributions to aging, including the recent development of an epigenetic "clock", and explore how antiaging therapies may work through epigenetic modifications.

Identification of Cartilage Microbial DNA Signatures and Associations With Knee and Hip Osteoarthritis.

Objective: Alterations of the gut microbiota have been implicated in many forms of arthritis, but an examination of cartilage microbial patterns has not been performed. This study was undertaken to characterize the microbial DNA profile of articular cartilage and determine changes associated with osteoarthritis (OA).

Methods: We performed 16S ribosomal RNA gene deep sequencing on eroded and intact cartilage samples from knee OA patients (n = 21 eroded and 21 intact samples) and hip OA patients (n = 34 eroded and 33 intact samples) and cadaver controls (n = 10 knee samples and 10 hip samples).

A pilot study of peripheral blood DNA methylation models as predictors of knee osteoarthritis radiographic progression: data from the Osteoarthritis Initiative (OAI).

Knee osteoarthritis (OA) is a leading cause of chronic disability worldwide, but no diagnostic or prognostic biomarkers are available. Increasing evidence supports epigenetic dysregulation as a contributor to OA pathogenesis. In this pilot study, we investigated epigenetic patterns in peripheral blood mononuclear cells (PBMCs) as models to predict future radiographic progression in OA patients enrolled in the longitudinal Osteoarthritis Initiative (OAI) study.

Epigenetic editing: How cutting-edge targeted epigenetic modification might provide novel avenues for autoimmune disease therapy.

Autoimmune diseases are enigmatic and complex, and most been associated with epigenetic changes. Epigenetics describes changes in gene expression related to environmental influences mediated by a variety of effectors that alter the three-dimensional structure of chromatin and facilitate transcription factor or repressor binding. Recent years have witnessed a dramatic change and acceleration in epigenetic editing approaches, spurred on by the discovery and later development of the CRISPR/Cas9 system as a highly modular and efficient site-specific DNA binding domain.

Epigenetics and Bone Remodeling.

Purpose Of Review: Bone remodeling is a diverse field of study with many direct clinical applications; past studies have implicated epigenetic alterations as key factors of both normal bone tissue development and function and diseases of pathologic bone remodeling. The purpose of this article is to review the most important recent advances that link epigenetic changes to the bone remodeling field.

Recent Findings: Epigenetics describes three major phenomena: DNA modification via methylation, histone side chain modifications, and short non-coding RNA sequences which work in concert to regulate gene transcription in a heritable fashion.

The Epigenomic Landscape in Osteoarthritis.

Purpose Of Review: Epigenomics has emerged as a key player in our rapidly evolving understanding of osteoarthritis. Historical studies implicated epigenetic alterations, particularly DNA methylation, in OA pathogenesis; however, recent technological advances have resulted in numerous epigenome-wide studies examining in detail epigenetic modifications in OA. The purpose of this article is to introduce basic concepts in epigenetics and their recent applications to the study of osteoarthritis development and progression.

Genome-Wide DNA Methylation Study Identifies Significant Epigenomic Changes in Osteoarthritic Subchondral Bone and Similarity to Overlying Cartilage.

Objective: To perform a genome-wide DNA methylation study to identify differential DNA methylation patterns in subchondral bone underlying eroded and intact cartilage from patients with hip osteoarthritis (OA) and to compare these with DNA methylation patterns in overlying cartilage.

Methods: Genome-wide DNA methylation profiling using Illumina HumanMethylation 450 arrays was performed on eroded and intact cartilage and subchondral bone from within the same joint of 12 patients undergoing hip arthroplasty. Genes with differentially methylated CpG sites were analyzed to identify shared pathways, upstream regulators, and overrepresented gene ontologies, and these patterns were compared with those of the overlying cartilage.

DNA methylation patterns in naïve CD4+ T cells identify epigenetic susceptibility loci for malar rash and discoid rash in systemic lupus erythematosus.

Objective: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by heterogeneous clinical manifestations, autoantibody production and epigenetic dysregulation in T cells. We sought to investigate the epigenetic contribution to the development of cutaneous manifestations in SLE.

Methods: We performed genome-wide DNA methylation analyses in patients with SLE stratified by a history of malar rash, discoid rash or neither cutaneous manifestation, and age, sex and ethnicity matched healthy controls.

Renal involvement in lupus is characterized by unique DNA methylation changes in naïve CD4+ T cells.

Systemic lupus erythematosus is a multi-system disease characterized by wide-spread DNA methylation changes. To identify epigenetic susceptibility loci for lupus nephritis, genome-wide DNA methylation changes in naïve CD4+ T cells were compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients (28 with renal involvement and 28 without renal involvement), and 56 age-, sex-, and ethnicity-matched healthy controls were included in our study.

Autoimmune disease in the epigenetic era: how has epigenetics changed our understanding of disease and how can we expect the field to evolve?

Autoimmune diseases are complex and enigmatic, and have presented particular challenges to researchers seeking to define their etiology and explain progression. Previous studies have implicated epigenetic influences in the development of autoimmunity. Epigenetics describes changes in gene expression related to environmental influences without alterations in the underlying genomic sequence, generally classified into three main groups: cytosine genomic DNA methylation, modification of various sidechain positions of histone proteins and noncoding RNAs feedback.

Genome-wide DNA methylation study identifies significant epigenomic changes in osteoarthritic cartilage.

Objective: To perform a genome-wide DNA methylation study to identify DNA methylation changes in osteoarthritic (OA) cartilage tissue.

Methods: The contribution of differentially methylated genes to OA pathogenesis was assessed by bioinformatic analysis, gene expression analysis, and histopathologic severity correlation. Genome-wide DNA methylation profiling of >485,000 methylation sites was performed on eroded and intact cartilage from within the same joint of 24 patients undergoing hip arthroplasty for OA.

Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naïve CD4+ T cells from lupus patients.

Systemic lupus erythematosus is an autoimmune disease characterized by multi-system involvement and autoantibody production. Abnormal T cell DNA methylation and type-I interferon play an important role in the pathogenesis of lupus. We performed a genome-wide DNA methylation study in two independent sets of lupus patients and matched healthy controls to characterize the DNA methylome in naïve CD4+ T cells in lupus.

Functional characterization of the MECP2/IRAK1 lupus risk haplotype in human T cells and a human MECP2 transgenic mouse.

Genetic polymorphism in MECP2/IRAK1 on chromosome Xq28 is a confirmed and replicated susceptibility locus for lupus. High linkage disequilibrium in this locus suggests that both MECP2 and IRAK1 are candidate genes for the disease. DNA methylation changes in lupus T cells play a central role in the pathogenesis of lupus, and MeCp-2 (encoded by MECP2) is a master regulator of gene expression and is also known to recruit DNA methyltransferase 1 (DNMT1) during DNA synthesis.

Epigenetics in systemic lupus erythematosus: leading the way for specific therapeutic agents.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder of an unclearly determined etiology. Past studies, both epidemiological and biological, have implicated epigenetic influences in disease etiology and pathogenesis. Epigenetics describes changes in gene expression not linked to alterations in the underlying genomic sequence, and is most often typified by three modifications: methylation of DNA, addition of various side chains to histone groups and transcriptional regulation via short ncRNA sequences.

Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus.

Systemic lupus erythematosus is a chronic-relapsing autoimmune disease of incompletely understood etiology. Recent evidence strongly supports an epigenetic contribution to the pathogenesis of lupus. To understand the extent and nature of dysregulated DNA methylation in lupus T cells, we performed a genome-wide DNA methylation study in CD4 (+) T cells in lupus patients compared to normal healthy controls.