LAUSR

Articular cartilage protects and lubricates joints for smooth motion and transmission of loads. Due to its high water content, chondrocytes within the cartilage are exposed to high levels of hydrostatic pressure, which has been shown to promote chondrocyte identity though unknown mechanisms. Here we investigate the effects of hydrostatic pressure on chondrocyte state and behavior, and discover that application of hydrostatic pressure promotes chondrocyte quiescence and prevents maturation towards the hypertrophic state. Mechanistically, hydrostatic pressure reduces H3K9me3-marked constitutive heterochromatin and concomitantly increases H3K27me3-marked facultative heterochromatin. Reduced H3K9me3 attenuates expression of pre-hypertrophic genes, replication, and transcription thereby reducing replicative stress. Conversely, promoting replicative stress by inhibition of topoisomerase II decreases Sox9 expression, suggesting that it enhances chondrocyte maturation. Our results reveal how hydrostatic pressure triggers chromatin remodeling to impact cell fate and function.