title: Downregulation of miR-221-3p contributes to IL-1β-induced cartilage degradation by directly targeting the SDF1/CXCR4 signaling pathway.
abstract: Osteoarthritis (OA) is characterized by degradation of chondrocyte extracellular matrix (ECM). Accumulating evidence suggests that microRNAs (miRNAs) are associated with OA, but little is known of their function in chondrocyte ECM degradation. The objective of this study was to investigate the expression and function of miRNAs in OA. miRNA expression profile was determined in OA cartilage tissues and controls, employing Solexa sequencing and reverse transcription quantitative PCR (RT-qPCR). According to a modified Mankin scale, cartilage degradation was evaluated. Functional analysis of the miRNAs on chondrocyte ECM degradation was performed after miRNA transfection and IL-1β treatment. Luciferase reporter assays and western blotting were employed to determine miRNA targets. Expression of miR-221-3p was downregulated in OA cartilage tissues, which was significantly correlated with a modified Mankin scale. Through gain-of-function and loss-of-function studies, miR-221-3p was shown to significantly affect matrix synthesis gene expression and chondrocyte proliferation and apoptosis. Using SW1353 and C28I2 cells, SDF1 was identified as a target of miR-221-3p. SDF1 overexpression resulted in increased expression of catabolic genes such as MMP-13 and ADAMTS-5 in response to IL-1β, but these effects were moderated by miR-221-3p. SDF1 treatment antagonized this effect, while knockdown of SDF1 by shSDF1 induced inhibitory effects on the expression of CXCR4 and its main target genes, similar to miR-221-3p. The results indicate that upregulation of miR-221-3p could prevent IL-1β-induced ECM degradation in chondrocytes. Targeting the SDF1/CXCR4 signaling pathway may be used as a therapeutic approach for OA. miR-221-3p is downregulated in human cartilage tissues. miR-221-3p levels are associated with cartilage degeneration grade. miR-221-3p upregulation prevents IL-1β-induced ECM degradation in chondrocytes. Protection of ECM degradation by miR-223-3p occurs via SDF1/CXCR4 signaling. miR-221-3p is identified as a novel potential therapeutic target for osteoarthritis. KEY MESSAGES: miR-221-3p is downregulated in human cartilage tissues. miR-221-3p levels are associated with cartilage degeneration grade. miR-221-3p upregulation prevents IL-1β-induced ECM degradation in chondrocytes. Protection of ECM degradation by miR-223-3p occurs via SDF1/CXCR4 signaling. miR-221-3p is identified as a novel potential therapeutic target for osteoarthritis.
authors.affiliation: Department of Orthopaedics, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road West, Xuzhou, 221006, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Orthopaedics, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road West, Xuzhou, 221006, China.
authors.forename: Feng-Chao
authors.initials: FC
authors.lastname: Zhao
authors.affiliation: Department of Orthopaedics, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road West, Xuzhou, 221006, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Pang
authors.affiliation: Department of Orthopaedics, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road West, Xuzhou, 221006, China.
authors.forename: Dong-Ya
authors.initials: DY
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road West, Xuzhou, 221006, China.
authors.forename: Sheng-Cheng
authors.initials: SC
authors.lastname: Yao
authors.affiliation: Department of Orthopaedics, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road West, Xuzhou, 221006, China.
authors.forename: Shao-Song
authors.initials: SS
authors.lastname: Sun
authors.affiliation: Department of Orthopaedics, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road West, Xuzhou, 221006, China. guokaijinxzm@163.com.
authors.forename: Kai-Jin
authors.initials: KJ
authors.lastname: Guo
mesh_terms: D000368:Aged; D002356:Cartilage / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics*; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010003:Osteoarthritis / Q000235:genetics* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D015398:Signal Transduction
chemical_list: D054377:Chemokine CXCL12; D018076:DNA, Complementary; D053583:Interleukin-1beta; D035683:MicroRNAs; D019718:Receptors, CXCR4; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C525709:MIR221, human
keywords: Il-1β; Osteoarthritis; SDF1/CXCR4 signaling pathway; miR-221-3p