Proteomics

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


ABSTRACT: Cartilage aging is a quintessential feature of knee osteoarthritis, and extracellular matrix (ECM) stiffening is a typical feature of cartilage aging. However, the mechanism of ECM stiffening to influence chondrocytes and downstream molecules is still poorly understood. Here, we mimicked the physiological and pathological stiffness of human cartilage by using polydimethylsiloxane-based substrates. We show that the epigenetic regulation of Parkin by histone deacetylase 3 (HDAC3) represents a new mechanosensitive mechanism by which the stiff matrix affects the physiology of chondrocytes. We found that ECM stiffening could accelerate the senescence of cultured chondrocytes in vitro, and also found that stiff ECM downregulated HDAC3, drove Parkin acetylation to activate excessive mitophagy, and accelerated chondrocyte senescence and osteoarthritis in mice. In contrast, intra-articular injection of adeno-associated virus expressing HDAC3 restored the young phenotype of aged chondrocytes stimulated by ECM stiffening and alleviated osteoarthritis in mice. Our findings indicate that changes in the mechanical properties of ECM initiate pathogenic mechanotransduction signals, promote the acetylation of Parkin and hyperactivate mitophagy, and damage the health of chondrocytes. These findings may provide new insights into how the mechanical properties of ECM regulate chondrocytes.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Cell Culture

SUBMITTER: lp wang  

LAB HEAD: bowen fu

PROVIDER: PXD046993 | Pride | 2024-06-16

REPOSITORIES: Pride

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

Fu Bowen B   Shen Jianlin J   Zou Xuenong X   Sun Nian N   Zhang Ze Z   Liu Zengping Z   Zeng Canjun C   Liu Huan H   Huang Wenhua W  

Bone research 20240524 1


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  ...[more]

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