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KLF9-GRK5-HDAC6 axis aggravates osteoarthritis pathogenesis by promoting chondrocyte extracellular matrix degradation and apoptosis

ABSTRACT: KLF9-GRK5-HDAC6 axis aggravates osteoarthritis pathogenesis by promoting chondrocyte extracellular matrix degradation and apoptosis

PROVIDER: PRJNA1202090 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31808402_1.fastq.gz	Fastqsanger.gz
	SRR31808402_2.fastq.gz	Fastqsanger.gz
	SRR31808403_1.fastq.gz	Fastqsanger.gz
	SRR31808403_2.fastq.gz	Fastqsanger.gz
	SRR31808404_1.fastq.gz	Fastqsanger.gz

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KLF9-GRK5-HDAC6 axis aggravates osteoarthritis pathogenesis by promoting chondrocyte extracellular matrix degradation and apoptosis

Project description:Osteoarthritis (OA) is a degenerative joint disease that affects the cartilage and surrounding tissues. The transcription factor Kruppel-like family factor 9 (KLF9) has been identified as a regulator of tumorigenesis. However, its role in OA is still not fully understood. Herein, this study aimed to access the potential role and molecular mechanism by which KLF9 regulates OA development. KLF9 was upregulated in cartilage tissues of OA patients and medial meniscotibial ligament (MMTL)-induced OA rats, as well as in IL-1β-treated chondrocytes. Furthermore, knockdown of KLF9 inhibited OA-related cartilage injury, as evidenced by inhibiting chondrocyte extracellular matrix (ECM) degradation, increasing chondrocyte viability, and decreasing apoptosis. Conversely, overexpression of KLF9 had the opposite effect. The downstream mechanism of KLF9 was confirmed. KLF9 mediated the transcription of G protein-coupled receptor kinase 5 (GRK5) by directly targeting the GRK5 promoter. GRK5 knockdown eliminated the effects of KLF9 overexpression on chondrocyte dysfunction. It was also found that GRK5 combined with histone deacetylase 6 (HDAC6) and promoted HDAC6 phosphorylation. The use of the HDAC6 inhibitor TubastatinA also abolished the effects of GRK5 overexpression on chondrocyte ECM degradation and apoptosis. These results demonstrate that the KLF9-GRK5-HDAC6 axis plays a crucial role in promoting the progression of OA.

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Project description:Chondrocyte senescence underlies osteoarthritis (OA). However, the pathogenesis of chondrocyte senescence remains largely unclear. Here we report that TRIM15 is a critical regulator in chondrocyte senescence. TIRM15 is highly expressed in chondrocytes of senescent cartilage from human OA patients and aged mice. Using gain- and loss-of-function studies, we further identify that TRIM15 facilitates chondrocyte senescence. Notably, conditional deletion of TRIM15 in chondrocytes severely impairs skeletal growth, partially due to the fact that embryonic chondrocyte senescence is disturbed. Compared with Col2a1-CreERT2/TRIM15flox/flox mice, TRIM15flox/flox mice exhibits accelerated OA phenotype, increased senescence markers and senescence-associated secretory phenotype (SASP) during aging. Mechanistically, TRIM15 binds with YAP and directly mediates K48-linked YAP ubiquitination at K254, which interrupts the interaction between YAP and AMOT, leading to enhanced YAP nuclear translocation. Intra-articular injection of AAV5-Trim15 shRNA decelerates OA progression in mice. Collectively, these findings indicate that targeting TRIM15 reshapes aging cartilage microenvironment and protects against OA.

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Project description: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.

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