title: MicroRNA-455-3p modulates cartilage development and degeneration through modification of histone H3 acetylation.
abstract: Histone acetylation regulated by class I histone deacetylases (HDACs) plays a pivotal role in matrix-specific gene transcription and cartilage development. While we previously demonstrated that microRNA (miR)-455-3p is upregulated during chondrogenesis and can enhance early chondrogenesis, the mechanism underlying this process remains largely unclear. In this study, we characterized the effect of miR-455-3p on histone H3 acetylation and its role during cartilage development and degeneration. We observed that miR-455-3p was highly expressed in proliferating and pre-hypertrophic chondrocytes, while HDAC2 and HDAC8 were primarily expressed in hypertrophic chondrocytes. Meanwhile, miR-455-3p suppressed the activity of reporter constructs containing the 3'-untranslated regions of HDAC2/8, inhibited HDAC2/8 expression and promoted histone H3 acetylation at the collagen 2 (COL2A1) promoter in human SW1353 chondrocyte-like cells. Treatment with the HDAC inhibitor trichostatin A (TSA) resulted in increased expression of cartilage-specific genes and promoted glycosaminoglycan deposition. Moreover, TSA inhibited matrix metalloproteinase 13 (Mmp13) expression and promoted nuclear translocation of SOX9 in interleukin-1-treated primary mouse chondrocytes. Lastly, knockdown of HDAC2/3/8 increased SRY (sex-determining region Y)-box 9 (SOX9) and decreased Runt-related transcription factor 2 (RUNX2) expression. Taken together, these findings suggest that miR-455-3p plays a critical role during chondrogenesis by directly targeting HDAC2/8 and promoting histone H3 acetylation, which raises possibilities of using miR-455-3p to influence chondrogenesis and cartilage degeneration.
authors.affiliation: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Weishen
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Urology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Lingwu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Ziji
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Fangang
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Guangxin
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Puyi
authors.initials: P
authors.lastname: Sheng
authors.affiliation: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Electronic address: zhzhiqi@mail.sysu.edu.cn.
authors.forename: Zhiqi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Electronic address: liaowmsysu@163.com.
authors.forename: Weiming
authors.initials: W
authors.lastname: Liao
mesh_terms: D020413:3' Untranslated Regions; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002356:Cartilage / Q000166:cytology / Q000378:metabolism; D045744:Cell Line, Tumor; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020219:Chondrogenesis / Q000187:drug effects / Q000235:genetics*; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; C499177:COL2A1 protein, human; D024043:Collagen Type II; D050659:Core Binding Factor Alpha 1 Subunit; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007375:Interleukin-1; C583404:MIRN455 microRNA, human; C574091:MIRN455 microRNA, mouse; D035683:MicroRNAs; D012097:Repressor Proteins; C493716:Runx2 protein, mouse; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; C012589:trichostatin A; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C533423:HDAC2 protein, human; C409470:HDAC8 protein, human; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases
keywords: Cartilage-specific genes; Chondrogenesis; Class I HDACs; Histone acetylation; miR-455-3p