title: Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2.
abstract: MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis (OA) pathogenesis. In our study, a real-time PCR assay revealed that miR-483-5p was upregulated in articular cartilage from OA patients and experimental OA mice induced by destabilization of the medial meniscus compared to their controls. Overexpression of miR-483-5p by intra-articular injection of lentivirus LV3-miR-483-5p significantly enhanced the severity of experimental OA. Consequently, we synthesized antago-miR-483-5p to silence the endogenous miR-483-5p and delivered it intra-articularly, which revealed that antago-miR-483-5p delayed the progression of experimental OA. To investigate the functional mechanism of miR-483-5p in OA development, we generated doxycycline-inducible miR-483 transgenic (TG483) mice. TG483 mice exhibited significant acceleration and increased severity of OA, and age-related OA occurred with higher incidence and greater severity in TG483 mice compared with their controls. Furthermore, our results revealed miR-483-5p directly targeted to the cartilage matrix protein matrilin 3 (Matn3) and tissue inhibitor of metalloproteinase 2 (Timp2) to stimulate chondrocyte hypertrophy, extracellular matrix degradation, and cartilage angiogenesis, and it consequently initiated and accelerated the development of OA. In conclusion, our findings reveal an miRNA functional pathway important for OA development. Targeting of miR-483-5p by intra-articular injection of antago-miR-483-5p represents an approach that could prevent the onset of OA and delay its progression.
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Tropical Diseases and Translational Medicine of The Ministry of Education, Hainan Medical College, Haikou 571199, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors.forename: Qiuyi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Orthopedics, General Hospital of Guangzhou Military Command of PLA, Guangzhou 510010, China.
authors.forename: Jincheng
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Orthopedics, General Hospital of Guangzhou Military Command of PLA, Guangzhou 510010, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors.forename: Shenqiu
authors.initials: S
authors.lastname: Luo
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China. Electronic address: zengdavid@126.com.
authors.forename: Chun
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China. Electronic address: daozhang@medmail.com.cn.
authors.forename: Daozhang
authors.initials: D
authors.lastname: Cai
authors.affiliation: Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China. Electronic address: baixc15@smu.edu.cn.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Bai
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000070416:Antagomirs / Q000008:administration & dosage / Q000235:genetics*; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D064235:Matrilin Proteins / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*; D055815:Young Adult
chemical_list: D000070416:Antagomirs; D064235:Matrilin Proteins; D035683:MicroRNAs; C548913:Mirn483 microRNA, mouse; D019716:Tissue Inhibitor of Metalloproteinase-2
keywords: antago-miR-483-5p; cartilage angiogenesis; chondrocyte; hypertrophy; matrilin 3; osteoarthritis; tissue inhibitor of metalloproteinase 2