Abstract
ABSTRACTArticular cartilage protects and lubricates joints for smooth motion and transmission of loads. Owing 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 through 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 the amount of trimethylated H3K9 (K3K9me3)-marked constitutive heterochromatin and concomitantly increases H3K27me3-marked facultative heterochromatin. Reduced levels of 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.This article has an associated First Person interview with the first author of the paper.
Highlights
The ends of long bones at the regions of joints are covered by a specialized connective tissue termed articular cartilage; a resilient, smooth and elastic tissue with a low frictional coefficient that protects and lubricates joints for smooth motion and transmission of loads
We discover that application of cyclic hydrostatic pressure promotes chondrocyte quiescence and a Sox9high immature state through a reduction of trimethylated H3K9 (H3K9me3)-marked constitutive heterochromatin, with a concomitant increase in H3K27me3-marked facultative heterochromatin
We observe that cyclic hydrostatic pressure (HP) mimicking physiological loading of the articular cartilage leads to decreased nuclear volume, chromatin decompaction, and promotion of a quiescent, less mature chondrocyte state, similar to what is found in vivo on the surface zone of the articular cartilage
Summary
The ends of long bones at the regions of joints are covered by a specialized connective tissue termed articular cartilage; a resilient, smooth and elastic tissue with a low frictional coefficient that protects and lubricates joints for smooth motion and transmission of loads. Articular cartilage lacks blood vessels, lymphatics and nerves, and despite being subject to a harsh biomechanical environment, it has. Handling Editor: Andrew Ewald Received 15 April 2020; Accepted 1 December 2020 limited capacity for intrinsic healing and repair. In this regard, the preservation of healthy articular cartilage is of critical importance for joint function (Kobayashi and Kronenberg, 2014). Chondrocytes undergo proliferation and terminal differentiation to hypertrophic chondrocytes, and subsequently osteoblasts, to form bone in a process termed endochondral ossification (Tsang and Cheah, 2019)
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