STIMULATION OF DEACETYLATION OF Β-CATENIN IN OSTEOARTHRITIS CHONDROCYTES CAN REVERSE CHON DROGENIC DEGENERATION CAUSED BY MITOCHONDRIAL DYSFUNCTION OF CHONDROCYTE
Main Article Content
Keywords
leptin, β-catenin acetylation, Wnt/β-catenin, HDAC1
Abstract
Obesity is an important contributing factor to osteoarthritis (OA), characterized by cartilage thinning and disintegration, inflammation and cartilage remodeling, accompanied by dysfunction of chondrocyte metabolism and mitochondrial biology. The aim of our study was to investigate the role of adipokine (leptin) -mediated β-catenin in the development and progression of OA, with a focus on the relationship between degenerative chondrocyte mitochondrial dysfunction and the Wnt/β-catenin pathway. Our data suggest that β-catenin acetylation modification is low in normal chondrocytes. However, in leptin mediated chondrocytes, down-regulated HDAC1 led to increased β-catenin acetylation of Lys-49, and increased downstream β-catenin phosphorylation promoted nuclear translocation and activated the β-catenin/WNT signaling pathway. The activation of mitochondrial dysfunction and cell death programs in OA chondrocytes. Functional analysis showed that leptin enhanced mitochondrial division, resulting in ROS overproduction, mitochondrial pro-apoptotic protein leakage, and Caspase-9-dependent cell death pathway activation. However, overexpression of HDAC1 blocks the progression of mitochondrial division while activating chondrocyte pro- survival signaling. At the molecular level, our data further suggest that the Wnt/β-catenin pathway is required for chondrocyte protective mechanisms resulting from HDAC1 overexpression: Inhibition of Wnt/β-catenin pathway by promoting β-catenin deacetylation can reduce mitochondrial fission, metabolic function changes and activation of apoptotic signals in chondrocytes. Overall, our data suggest that obesity-induced osteoarthritis is associated with HDAC1 downregulation, Wnt/β-catenin pathway deacetylation inactivation and mitochondrial dysfunction, and Caspase-9-dependent cell death activation. Based on this, enhancement of HDAC1 activity and inhibition of Wnt/β-catenin signaling pathway to stimulate deacetylation of β-catenin in osteoarthritis chondrocytes can reverse cartilage degeneration caused by mitochondrial dysfunction of chondrocytes..
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Xiaodong Fu
Department of Orthopedics, the Second Affiliated Hospital of Soochow University
Xiaomiao Li
Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiaotong University
Yi Shen
Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiaotong University
Jun Yan
Department of Orthopedics, the Second Affiliated Hospital of Soochow University