Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3OAMEDLINE
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.
Bowen Fu;Jianlin Shen;Xuenong Zou;Nian Sun;Ze Zhang;Zengping Liu;Canjun Zeng;Huan Liu;Wenhua Huang;
Guangdong Medical Innovation Platform for Translation of 3D Printing Application,The Third Affiliated Hospital,Southern Medical University,Guangzhou 510630 Guangdong,China Guangdong Engineering Research Center for Translation of Medical 3D Printing Application,Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics,National Key Discipline of Human Anatomy,School of Basic Medical Sciences,Southern Medical University,Guangzhou 510145 Guangdong,China Department of Foot and Ankle Surgery,Center for Orthopedic Surgery,The Third Affiliated Hospital,Southern Medical University,Guangzhou 510630 Guangdong,ChinaDepartment of Orthopedics,Affiliated Hospital of Putian University,Putian 351100 Fujian,China Central Laboratory,Affiliated Hospital of Putian University,Putian 351100 Fujian,ChinaGuangdong Provincial Key Laboratory of Orthopedics and Traumatology,Department of Spinal Surgery,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou 510080 Guangdong,ChinaNanfang Hospital,Southern Medical University,Guangzhou 510515 Guangdong,China Guangzhou Blood Center,Guangzhou 510095 Guangdong,ChinaDepartment of Orthopedics,The Affiliated Traditional Chinese Medicine Hospital,Southwest Medical University,Luzhou 646000 Sichuan,China
临床医学
chondrocyteosteoarthritisstiffness
《Bone Research》 2024 (002)
P.438-452 / 15
supported by the National Key R&D Program of China(2022YFB4600600);National Natural Science Foundation of China(32271181,82301785);Guangdong Basic and Applied Basic Research Foundation(2020B1515120001);Sichuan Province Central Guided Local Science and Technology Development Special Program(2023ZYD0072).
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