title: Mechanical and IL-1β Responsive miR-365 Contributes to Osteoarthritis Development by Targeting Histone Deacetylase 4.
abstract: Mechanical stress plays an important role in the initiation and progression of osteoarthritis. Studies show that excessive mechanical stress can directly damage the cartilage extracellular matrix and shift the balance in chondrocytes to favor catabolic activity over anabolism. However, the underlying mechanism remains unknown. MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis pathogenesis. We have found that mechanical loading up-regulated microRNA miR-365 in growth plate chondrocytes, which promotes chondrocyte differentiation. Here, we explored the role of the mechanical responsive microRNA miR-365 in pathogenesis of osteoarthritis (OA). We found that miR-365 was up-regulated by cyclic loading and IL-1β stimulation in articular chondrocytes through a mechanism that involved the transcription factor NF-κB. miR-365 expressed significant higher level in rat anterior cruciate ligament (ACL) surgery induced OA cartilage as well as human OA cartilage from primary OA patients and traumatic OA Patients. Overexpression of miR-365 in chondrocytes increases gene expression of matrix degrading enzyme matrix metallopeptidase 13 (MMP13) and collagen type X (Col X). The increase in miR-365 expression in OA cartilage and in response to IL-1 may contribute to the abnormal gene expression pattern characteristic of OA. Inhibition of miR-365 down-regulated IL-1β induced MMP13 and Col X gene expression. We further showed histone deacetylase 4 (HDAC4) is a direct target of miR-365, which mediates mechanical stress and inflammation in OA pathogenesis. Thus, miR-365 is a critical regulator of mechanical stress and pro-inflammatory responses, which contributes cartilage catabolism. Manipulation of the expression of miR-365 in articular chondrocytes by miR-365 inhibitor may be a potent therapeutic target for the prevention and treatment of osteoarthritis.
authors.affiliation: Department of Orthopedics, the Affiliated Hospital of Qingdao University, 1677 Wutaishan Rd, Qingdao 266000, China. xu_yang0608@outlook.com.
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Cell and Molecular Biology Laboratory, Department of Orthopedics, Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI 02903, USA. yingjie_guan@brown.edu.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Orthopedics, the Affiliated Hospital of Qingdao University, 1677 Wutaishan Rd, Qingdao 266000, China. shaoqi99@aliyun.com.
authors.forename: Shaoqi
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department of Orthopedics, the Affiliated Hospital of Qingdao University, 1677 Wutaishan Rd, Qingdao 266000, China. wangyuanhe-2004@163.com.
authors.forename: Yuanhe
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, the Affiliated Hospital of Qingdao University, 1677 Wutaishan Rd, Qingdao 266000, China. kangsun1@outlook.com.
authors.forename: Kang
authors.initials: K
authors.lastname: Sun
authors.affiliation: Cell and Molecular Biology Laboratory, Department of Orthopedics, Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI 02903, USA. qian_chen@brown.edu.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000368:Aged; D000818:Animals; D002358:Cartilage, Articular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D006655:Histone Deacetylases / Q000235:genetics / Q000276:immunology; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D016328:NF-kappa B / Q000276:immunology; D010003:Osteoarthritis / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D013314:Stress, Mechanical; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D053583:Interleukin-1beta; C546819:MIRN365 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D012097:Repressor Proteins; D053509:Matrix Metalloproteinase 13; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
keywords: inflammation; mechanical loading; miR-365; osteoarthritis