The Articular Chromatin Landscape in Osteoarthritis

Recent technological breakthroughs have enabled multidimensional phenotyping, with unprecedented single-cell resolution and genome-wide coverage, across multiple osteoarthritis (OA)-relevant tissues, such as articular cartilage, synovium, infrapatellar fat pad, and subchondral bone. The majority of the single nucleotide variations (SNVs) that have been associated with OA are located in non-protein coding regions and confer risk for disease by altering the expression level, instead of the amino acid sequence of the gene product. These data have shaped the concept of OA as a polygenic disease, where genetic factors disrupt the chromatin landscape in disease-relevant cells, leading to aberrant expression of effector genes. Pharmacologic manipulation of the OA-driving epigenetic landscape has recently emerged as an attractive path for the development of disease-modifying drugs. Novel clustered regulatory interspaced short palindromic repeats (CRISPR)-based technologies provide opportunities for precise epigenetic editing at the desired genomic regions and may allow a targeted transcriptional regulation of disease-relevant genes in disease-relevant cells. The aim of the present narrative review is to summarize the emerging data on the role of epigenetic factors and chromatin structure as calibrators of the risk for developing OA and to discuss the opportunities and challenges arising from the use of chromatin landscape to guide drug discovery.