Epigenetic Therapies for Osteoarthritis

Despite its prevalence, osteoarthritis (OA) has no clinically approved disease-modifying drug. Numerous drug development efforts focused on single molecules or pathways have failed, signifying the need for multiple gene/protein pathway correction. Several epigenetic regulators that affect large gene networks have been demonstrated to play a role in OA pathogenesis. Targeting these epigenetic regulators as disease modifying OA drugs (DMOADs) holds the potential to reset the aberrant epigenetic landscape found in OA tissues and rewire gene networks. Identifying targeting cofactors can enhance specificity of these new epigenetic drugs. Osteoarthritis (OA) is an age-associated disease characterized by chronic joint pain resulting from degradation of articular cartilage, inflammation of the synovial lining, and changes to the subchondral bone. Despite the wide prevalence, no FDA-approved disease-modifying drugs exist. Recent evidence has demonstrated that epigenetic dysregulation of multiple molecular pathways underlies OA pathogenesis, providing a new mechanistic and therapeutic axis with the advantage of targeting multiple deregulated pathways simultaneously. In this review, we focus on the epigenetic regulators that have been implicated in OA, their individual roles, and potential crosstalk. Finally, we discuss the pharmacological molecules that can modulate their activities and discuss the potential advantages and challenges associated with epigenome-based therapeutics for OA. Osteoarthritis (OA) is an age-associated disease characterized by chronic joint pain resulting from degradation of articular cartilage, inflammation of the synovial lining, and changes to the subchondral bone. Despite the wide prevalence, no FDA-approved disease-modifying drugs exist. Recent evidence has demonstrated that epigenetic dysregulation of multiple molecular pathways underlies OA pathogenesis, providing a new mechanistic and therapeutic axis with the advantage of targeting multiple deregulated pathways simultaneously. In this review, we focus on the epigenetic regulators that have been implicated in OA, their individual roles, and potential crosstalk. Finally, we discuss the pharmacological molecules that can modulate their activities and discuss the potential advantages and challenges associated with epigenome-based therapeutics for OA. BER is the primary DNA repair pathway in mammals. It is responsible for removing small base lesions, often derived from oxidation, alkylation, or other events. The process is started by a glycosylate that recognizes and removes the damaged base. In the context of DNA demethylation, this pathway is utilized first by the targeted oxidation of the base by the TET enzymes and then later this base is acted on by thymine DNA glycosylase (TDG). the developmental process by which long bones are formed. Cartilaginous tissue, formed by the condensation of mesenchymal stem cells, first lays down template for the developing bone. The chondrocytes go through a variety of stages of maturation, including proliferation and maturation into hypertrophic chondrocytes. At this final stage, the cells undergo apoptosis, leaving room for the invasion of the template by osteoblasts to form the final calcified bone. epigenetics is broadly defined as the changes ‘on top of’ (epi) the genome that influence the transcription of genes. While traditionally this has implied chemical changes to DNA or histones, this definition has been broadened to include chromatin folding and organization as well as different coding and noncoding RNAs that can interact with DNA and influence gene expression. the gene body is defined as the entire gene from the transcriptional start site (TSS) to the transcriptional end site. This includes both the exons and introns contained within the gene. the proteins around which DNA is wrapped to form nucleosomes. Histones can be chemically modified in a variety of ways, including methylation, acetylation, and phosphorylation. Depending on the particular histone modification, its positioning, and combination with other marks, the transcriptional machinery can be either recruited or excluded at these chromatin sites. these are responsible for the addition of a methyl group to lysine residues in histones. Depending on the context, this mark can either be activating (H3K79me/me2/me3) or repressive (H3K27me2/me3). Conversely, histone demethylases remove these methylation marks from the target histones. within the contexts of endochondral ossification, this refers to the process by which columnar chondrocytes mature and begin to produce different types of extracellular matrix proteins such as type X collagen. In addition, they begin to undergo apoptosis to make way for the new bone. These changes are controlled, in part, by the transcription factor RUNX2 and by WNT signaling. While a normal part of skeletal development, chondrocyte hypertrophy can also occur in OA, in which chondrocytes, which should normally make type II collagen, switch their fate. These changes are associated with pathology and change the mechanical properties of articular cartilage. several types of mouse OA models exist. In genetic models, a mutation in the mouse genome increases the rate of spontaneous OA, modeling human predisposition to the disease. Other models use surgical intervention to destabilize the joint, including destabilization of the medial meniscus (DMM), tearing of the anterior cruciate ligament (ACLT), or medial meniscectomy (MMx). These models generally represent post-traumatic OA.