Fig. 3

Cellular senescence and other age-related mechanisms in the knee joint lead to OA progression. Senescent chondrocytes promote the expression of the senescent phenotype by up-regulating SASP, CircRREB1, and ADAM19 and down-regulating PDZK1, SIRT6, and MYL3. Meanwhile, senescent chondrocytes also promote senescence in neighboring cells by secreting SASP and EVs (containing miR-34a, miR-24, and miR-150). In addition, ECM sclerosis downregulates HDAC3 and activates mitochondrial autophagy, leading to a chondrocyte senescence phenotype and accelerated OA symptoms. Depletion and aberrant repair of MSCs accelerate pathological changes in OA. Senescent MSCs presented decreased expression of PUM1, ALKBH5, and HP1α/LAP2. Senescent chondrocytes limit the pluripotency of MSCs, while MSCs accelerate the apoptosis of senescent chondrocytes. The absence of Gremlin 1⁺ cells may contribute to the progression of OA. Senescent SYCs accelerate senescence and cartilage damage by increasing NAD, SASP, PI3K/ERK, and TNF-α levels. Changes in subchondral bone cells with senescence in OA also promote OA progression. OCs accelerate intra-articular senescence and OA pathology by regulating COX2/PGE2, TGF-β1, HIF-1α, Lcp1, and Netrin-1. ECs, subchondral OCYs, and subchondral OBs activate OCs via RANKL and accelerate subchondral bone erosion. OBs release PGE2, IL-6, MMP-9, and VEGF to further promote OCs differentiation. Senescent ADs secrete SASP factors, accelerating the senescence of other cells and the progression of OA. Senescent satellite cells significantly inhibit musculoskeletal cell regeneration by unblocking p16. All of these factors contribute to the malignant crosstalk of senescence in OA and accelerate its progression. The red frames represent upregulated genes, and the blue frames represent down-regulated genes