title: AIMP1 downregulation restores chondrogenic characteristics of dedifferentiated/degenerated chondrocytes by enhancing TGF-β signal.
abstract: Dedifferentiation and degeneration of chondrocytes critically influences the efficiency of cartilage repair. One of the causes is the defect of transforming growth factor (TGF)-β signaling that promotes chondrogenic differentiation and degeneration. In the present study, we found that aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) negatively regulates TGF-β signaling via interactions with Smad2 and Smad3 in immunoprecipitation assay and luciferase assay. In addition, we observed that the AIMP1 expression level was significantly increased in osteoarthritis (OA) patient-derived degenerated chondrocytes compared with healthy control. So, we hypothesized that downregulation of AIMP1 using small-interfering RNA (siRNA) technology in dedifferentiated (collected at passage #6) and degenerated (obtained from OA-affected areas) chondrocytes could lead to recover TGF-β signaling in both chondrocytes. Indeed, AIMP1 downregulation restored TGF-β signaling by promoting phosphorylation of Smad2 and Smad3, which shows redifferentiated characteristics in both dedifferentiated and degenerated chondrocytes. Additionally, implantation analyses using in vivo mouse model clearly showed that AIMP1 downregulation resulted in the increased chondrogenic potential as well as the enhanced cartilage tissue formation in both dedifferentiated and degenerated chondrocytes. Histological analyses clarified that AIMP1 downregulation increased expression levels of collagen type II (Col II) and aggrecan, but not Col I expression. Taken together, these data indicate that AIMP1 downregulation using siRNA is a novel tool to restore TGF-β signaling and thereby increases the chondrogenic potential of dedifferentiated/degenerated chondrocytes, which could be further developed as a therapeutic siRNA to treat OA.
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea.|Department of Neurosurgery, Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: H
authors.initials: H
authors.lastname: Kumar
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: B-H
authors.initials: BH
authors.lastname: Cha
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: S
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Department of Neurosurgery, Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: I
authors.initials: I
authors.lastname: Han
authors.affiliation: Department of Pharmacy, College of Pharmacy, Ajou University, Suwon, Gyeonggi-do, Republic of Korea.
authors.forename: S G
authors.initials: SG
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000502:physiology; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C514492:Aimp1 protein, mouse; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C077219:small inducible cytokine subfamily E, member 1