title: TWIST1 induces MMP3 expression through up-regulating DNA hydroxymethylation and promotes catabolic responses in human chondrocytes.
abstract: The objective was to investigate the levels of TWIST1 in normal and OA cartilage and examine its role in regulating gene expression in chondrocytes. Human cartilage tissues and chondrocytes were obtained at autopsy from normal knee joints and from OA-affected joints at the time of total knee arthroplasty. TWIST1 expression was increased in human OA knee cartilage compared to normal knee cartilage. TWIST1 induced matrix metalloproteinase 3 (MMP3) expression without direct binding to MMP3 promoter and increased the 5-hydroxymethylcytosine (5hmC) level at the MMP3 promoter. The effect of TWIST1 on expression of TET family (TET1, 2 and 3) was measured in stable TWIST1 transfected TC28 cells, and TET1 expression was up-regulated. TWIST1 dependent upregulation of Mmp3 expression was suppressed in Tet triple KO fibroblast derived from mouse ES cells. Increased TWIST1 expression is a feature of OA-affected cartilage. We identified a novel mechanism of catabolic reaction where TWIST1 up-regulates MMP3 expression by enriching 5hmC levels at the MMP3 promoter via TET1 induction. These findings implicate TWIST1 as an important factor regulating OA related gene expression. Clarifying epigenetic mechanisms of 5hmC induced by TWIST1 is a critical molecule to understanding OA pathogenesis.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Hasei
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.|Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University, Faculty of Medicine, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Teramura
authors.affiliation: Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University, Faculty of Medicine, Osaka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takehara
authors.affiliation: Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University, Faculty of Medicine, Osaka, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Onodera
authors.affiliation: Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Horii
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Merissa
authors.initials: M
authors.lastname: Olmer
authors.affiliation: Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
authors.forename: Izuho
authors.initials: I
authors.lastname: Hatada
authors.affiliation: Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University, Faculty of Medicine, Osaka, Japan.|Department of Rehabilitation Medicine, Kindai University, Faculty of Medicine, Osaka, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Ozaki
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Lotz
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.|Department of Systems BioMedicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asahara
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D019175:DNA Methylation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020370:Osteoarthritis, Knee / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C103173:TWIST1 protein, human; D014409:Tumor Necrosis Factor-alpha; D051879:Twist-Related Protein 1; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3