Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3

Bowen Fu1,2,3, Jianlin Shen4,5, Xuenong Zou6, Nian Sun1,2,3, Ze Zhang7,8, Zengping Liu7,8, Canjun Zeng1,2,3, Huan Liu9, Wenhua Huang1,2,3

Bone Research ›› 2024, Vol. 12 ›› Issue (0) : 32. DOI: 10.1038/s41413-024-00333-9

Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3

  • Bowen Fu1,2,3, Jianlin Shen4,5, Xuenong Zou6, Nian Sun1,2,3, Ze Zhang7,8, Zengping Liu7,8, Canjun Zeng1,2,3, Huan Liu9, Wenhua Huang1,2,3
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Abstract

Extracellular matrix (ECM) stiffening is a typical characteristic of cartilage aging, which is a quintessential feature of knee osteoarthritis (KOA). However, little is known about how ECM stiffening affects chondrocytes and other molecules downstream. This study mimicked the physiological and pathological stiffness of human cartilage using polydimethylsiloxane (PDMS) substrates. It demonstrated that epigenetic Parkin regulation by histone deacetylase 3 (HDAC3) represents a new mechanosensitive mechanism by which the stiffness matrix affected chondrocyte physiology. We found that ECM stiffening accelerated cultured chondrocyte senescence in vitro, while the stiffness ECM downregulated HDAC3, prompting Parkin acetylation to activate excessive mitophagy and accelerating chondrocyte senescence and osteoarthritis (OA) in mice. Contrarily, intra-articular injection with an HDAC3-expressing adeno-associated virus restored the young phenotype of the aged chondrocytes stimulated by ECM stiffening and alleviated OA in mice. The findings indicated that changes in the mechanical ECM properties initiated pathogenic mechanotransduction signals, promoted the Parkin acetylation and hyperactivated mitophagy, and damaged chondrocyte health. These results may provide new insights into chondrocyte regulation by the mechanical properties of ECM, suggesting that the modification of the physical ECM properties may be a potential OA treatment strategy.

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Bowen Fu, Jianlin Shen, Xuenong Zou, Nian Sun, Ze Zhang, Zengping Liu, Canjun Zeng, Huan Liu, Wenhua Huang. Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3. Bone Research, 2024, 12(0): 32 https://doi.org/10.1038/s41413-024-00333-9

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Funding
Huan Liu (20016040@163.com) or Wenhua Huang (huangwenhua2009@139.com)

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