title: MicroRNA-222 regulates MMP-13 via targeting HDAC-4 during osteoarthritis pathogenesis.
abstract: BACKGROUND
  Even though increasing evidences on miRNA involvement in human pathological responses, the distinct roles and related mechanisms of miRNAs in the pathology of osteoarthritis (OA) are not yet fully understood.
  
  
  METHODS
  RNA levels or protein levels of Apoptotic genes, HDACs, MMP-13, and miRNAs in human chondrocytes isolated from normal biopsy sample and OA cartilages were analyzed by real-time PCR or western blotting. Exogenous modulation of miR-222 level was performed using delivery of its specific precursor or specific inhibitor and target validation assay was applied to identify its potent target. In vivo study using DMM mice model was performed and assessed the degree of cartilage degradation.
  
  
  RESULTS
  According to miRNA profiling, miR-222 was significantly down-regulated in OA chondrocytes. Over-expression of miR-222 significantly suppressed apoptotic death by down-regulating HDAC-4 and MMP-13 level. Moreover, 3'-UTR reporter assays showed that HDAC-4 is a direct target of miR-222. The treatment of chondrocytes with the HDAC inhibitor, trichostatin A (TSA), suppressed MMP-13 protein level and apoptosis, whereas the over-expression of HDAC-4 displayed opposite effects. The introduction of miR-222 into the cartilage of medial meniscus destabilized mice significantly reduced cartilage destruction and MMP-13 level.
  
  
  CONCLUSIONS
  Taken together, our data suggest that miR-222 may be involved in cartilage destruction by targeting HDAC-4 and regulating MMP-13 level.
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk 570-749, Korea.
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk 570-749, Korea.
authors.forename: Eun-Heui
authors.initials: EH
authors.lastname: Jin
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk 570-749, Korea.
authors.forename: Dongkyun
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Surgery, Wonkwang University School of Medicine, Iksan, Chunbuk 570-749, Korea.
authors.forename: Keun Young
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan, Chunbuk 570-749, Korea.
authors.forename: Churl-Hong
authors.initials: CH
authors.lastname: Chun
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk 570-749, Korea ; Integrated Omics Institute, Wonkwang University, Iksan, Chunbuk 570-749, Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Jin
keywords: Apoptosis; HDAC-4; Human chondrocytes; MMP-13; OA chondrocytes; miR-222