Abnormal epigenetics is the initial factor of the occurrence and development of osteoarthritis (OA), and abnormal mechanical load is a key pathogenic factor of OA. However, how abnormal mechanical load affects chondrocyte epigenetics is unclear. Chondrocytes reportedly respond to mechanics through the extracellular matrix (ECM), which has a role in regulating epigenetics in various diseases, and mitochondria are potential mediators of communication between mechanics and epigenetics. Therefore, it is hypothesized that the matrix mechanics of cartilage regulates their epigenetics through mitochondria and leads to OA. The matrix stiffness of OA cartilage on the stress-concentrated side increases, mitochondrial damage of chondrocyte is severe, and the chondrocyte H3K27me3 is demethylated. Moreover, mitochondrial permeability transition pore (mPTP) opens to increase the translocation of plant homeodomain finger protein 8 (Phf8) into the nucleus to catalyze H3K27me3 demethylation. This provides a new perspective for us to understand the mechanism of OA based on mechanobiology.