Expression of ADAMTS-4 by chondrocytes in the surface zone of human osteoarthritic cartilage is regulated by epigenetic DNA de-methylation
The two major aggrecanases involved in osteoarthritis (OA) are ADAMTS-4 and ADAMTS-5. Knock-out studies suggested that ADAMTS-5, but not ADAMTS-4, is the major aggrecanase in murine OA. However, studies of human articular cartilage suggest that ADAMTS-4 also contributes to aggrecan degradation in hu...
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| Veröffentlicht in: | Rheumatology international 2009-03, Vol.29 (5), p.525-534 |
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| description | The two major aggrecanases involved in osteoarthritis (OA) are ADAMTS-4 and ADAMTS-5. Knock-out studies suggested that ADAMTS-5, but not ADAMTS-4, is the major aggrecanase in murine OA. However, studies of human articular cartilage suggest that ADAMTS-4 also contributes to aggrecan degradation in human OA. This study investigated ADAMTS-4 in human OA. While ADAMTS-4 was virtually absent in control cartilage, numerous ADAMTS-4 immuno-positive chondrocytes were present in OA cartilage and their numbers increased with disease severity. RT-PCR confirmed expression, especially in the surface zone. DNA methylation was lost at specific CpG sites in the ADAMTS-4 promoter in OA chondrocytes, suggesting that the increased gene expression was more than a simple up-regulation, but involved loss of DNA methylation at specific CpG sites, resulting in a heritable and permanent expression of ADAMTS-4 in OA chondrocytes. These results suggest that ADAMTS-4 is epigenetically regulated and plays a role in aggrecan degradation in human OA. |
| doi_str_mv | 10.1007/s00296-008-0744-z |
| format | Article |
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C. ; Hashimoto, Ko ; Yamada, Norikazu ; Roach, Helmtrud I.</creator><creatorcontrib>Cheung, Kelvin S. C. ; Hashimoto, Ko ; Yamada, Norikazu ; Roach, Helmtrud I.</creatorcontrib><description>The two major aggrecanases involved in osteoarthritis (OA) are ADAMTS-4 and ADAMTS-5. Knock-out studies suggested that ADAMTS-5, but not ADAMTS-4, is the major aggrecanase in murine OA. However, studies of human articular cartilage suggest that ADAMTS-4 also contributes to aggrecan degradation in human OA. This study investigated ADAMTS-4 in human OA. While ADAMTS-4 was virtually absent in control cartilage, numerous ADAMTS-4 immuno-positive chondrocytes were present in OA cartilage and their numbers increased with disease severity. RT-PCR confirmed expression, especially in the surface zone. DNA methylation was lost at specific CpG sites in the ADAMTS-4 promoter in OA chondrocytes, suggesting that the increased gene expression was more than a simple up-regulation, but involved loss of DNA methylation at specific CpG sites, resulting in a heritable and permanent expression of ADAMTS-4 in OA chondrocytes. These results suggest that ADAMTS-4 is epigenetically regulated and plays a role in aggrecan degradation in human OA.</description><identifier>ISSN: 0172-8172</identifier><identifier>EISSN: 1437-160X</identifier><identifier>DOI: 10.1007/s00296-008-0744-z</identifier><identifier>PMID: 18941754</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>ADAM Proteins - genetics ; ADAM Proteins - metabolism ; ADAMTS4 Protein ; Aged ; Aged, 80 and over ; Cartilage ; Cartilage (articular) ; Cartilage, Articular - metabolism ; Chondrocytes - metabolism ; Chondrocytes - pathology ; Deoxyribonucleic acid ; DNA ; DNA Methylation ; Epigenesis, Genetic ; Female ; Fluorescent Antibody Technique, Indirect ; Gene Expression Regulation, Enzymologic ; Humans ; Immunohistochemistry ; Male ; Medicine ; Medicine & Public Health ; Original Article ; Osteoarthritis - genetics ; Osteoarthritis - metabolism ; Procollagen N-Endopeptidase - genetics ; Procollagen N-Endopeptidase - metabolism ; Rheumatology</subject><ispartof>Rheumatology international, 2009-03, Vol.29 (5), p.525-534</ispartof><rights>Springer-Verlag 2008</rights><rights>Springer-Verlag 2009</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c467t-30f0d4955f898eafdf408536159d8acdc1c8628cfe9d284a496cbeabc6ed6043</citedby><cites>FETCH-LOGICAL-c467t-30f0d4955f898eafdf408536159d8acdc1c8628cfe9d284a496cbeabc6ed6043</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00296-008-0744-z$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00296-008-0744-z$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,781,785,27926,27927,41490,42559,51321</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18941754$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cheung, Kelvin S. C.</creatorcontrib><creatorcontrib>Hashimoto, Ko</creatorcontrib><creatorcontrib>Yamada, Norikazu</creatorcontrib><creatorcontrib>Roach, Helmtrud I.</creatorcontrib><title>Expression of ADAMTS-4 by chondrocytes in the surface zone of human osteoarthritic cartilage is regulated by epigenetic DNA de-methylation</title><title>Rheumatology international</title><addtitle>Rheumatol Int</addtitle><addtitle>Rheumatol Int</addtitle><description>The two major aggrecanases involved in osteoarthritis (OA) are ADAMTS-4 and ADAMTS-5. Knock-out studies suggested that ADAMTS-5, but not ADAMTS-4, is the major aggrecanase in murine OA. However, studies of human articular cartilage suggest that ADAMTS-4 also contributes to aggrecan degradation in human OA. This study investigated ADAMTS-4 in human OA. While ADAMTS-4 was virtually absent in control cartilage, numerous ADAMTS-4 immuno-positive chondrocytes were present in OA cartilage and their numbers increased with disease severity. RT-PCR confirmed expression, especially in the surface zone. DNA methylation was lost at specific CpG sites in the ADAMTS-4 promoter in OA chondrocytes, suggesting that the increased gene expression was more than a simple up-regulation, but involved loss of DNA methylation at specific CpG sites, resulting in a heritable and permanent expression of ADAMTS-4 in OA chondrocytes. These results suggest that ADAMTS-4 is epigenetically regulated and plays a role in aggrecan degradation in human OA.</description><subject>ADAM Proteins - genetics</subject><subject>ADAM Proteins - metabolism</subject><subject>ADAMTS4 Protein</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Cartilage</subject><subject>Cartilage (articular)</subject><subject>Cartilage, Articular - metabolism</subject><subject>Chondrocytes - metabolism</subject><subject>Chondrocytes - pathology</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>Epigenesis, Genetic</subject><subject>Female</subject><subject>Fluorescent Antibody Technique, Indirect</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Original Article</subject><subject>Osteoarthritis - genetics</subject><subject>Osteoarthritis - metabolism</subject><subject>Procollagen N-Endopeptidase - genetics</subject><subject>Procollagen N-Endopeptidase - metabolism</subject><subject>Rheumatology</subject><issn>0172-8172</issn><issn>1437-160X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp9kc-O0zAQxi0EYsvCA3BBFgf2ZBgnjmMfq_0DSAsc6IGb5dqTJqskLnYi0T4CT42jVloJCS62R_P7vtH4I-Q1h_ccoP6QAAotGYBiUAvBjk_IiouyZlzCj6dkBbwumMrHBXmR0gPkWkp4Ti640oLXlViR37e_9hFT6sJIQ0PXN-svm-9M0O2BujaMPgZ3mDDRbqRTizTNsbEO6TGMuPDtPNgsTBMGG6c2dlPnqMvPrrc7pF2iEXdzbyf0iyXuux2OuEA3X9fUIxtwag-5n-e_JM8a2yd8db4vyebudnP9id1_-_j5en3PnJD1xEpowAtdVY3SCm3jGwGqKiWvtFfWecedkoVyDWpfKGGFlm6LduskegmivCRXJ9t9DD9nTJMZuuSw7-2IYU5GQ83rkquFfPdfUkotQYsqg2__Ah_CHMe8hFFK8KLKP58hfoJcDClFbMw-doONB8PBLHGaU5wmx2mWOM0xa96cjeftgP5Rcc4vA8UJSLk17jA-Tv636x8rxKzU</recordid><startdate>20090301</startdate><enddate>20090301</enddate><creator>Cheung, Kelvin S. C.</creator><creator>Hashimoto, Ko</creator><creator>Yamada, Norikazu</creator><creator>Roach, Helmtrud I.</creator><general>Springer-Verlag</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>7QP</scope><scope>7TM</scope></search><sort><creationdate>20090301</creationdate><title>Expression of ADAMTS-4 by chondrocytes in the surface zone of human osteoarthritic cartilage is regulated by epigenetic DNA de-methylation</title><author>Cheung, Kelvin S. C. ; Hashimoto, Ko ; Yamada, Norikazu ; Roach, Helmtrud I.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c467t-30f0d4955f898eafdf408536159d8acdc1c8628cfe9d284a496cbeabc6ed6043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>ADAM Proteins - genetics</topic><topic>ADAM Proteins - metabolism</topic><topic>ADAMTS4 Protein</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Cartilage</topic><topic>Cartilage (articular)</topic><topic>Cartilage, Articular - metabolism</topic><topic>Chondrocytes - metabolism</topic><topic>Chondrocytes - pathology</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA Methylation</topic><topic>Epigenesis, Genetic</topic><topic>Female</topic><topic>Fluorescent Antibody Technique, Indirect</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Original Article</topic><topic>Osteoarthritis - genetics</topic><topic>Osteoarthritis - metabolism</topic><topic>Procollagen N-Endopeptidase - genetics</topic><topic>Procollagen N-Endopeptidase - metabolism</topic><topic>Rheumatology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cheung, Kelvin S. 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C.</au><au>Hashimoto, Ko</au><au>Yamada, Norikazu</au><au>Roach, Helmtrud I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Expression of ADAMTS-4 by chondrocytes in the surface zone of human osteoarthritic cartilage is regulated by epigenetic DNA de-methylation</atitle><jtitle>Rheumatology international</jtitle><stitle>Rheumatol Int</stitle><addtitle>Rheumatol Int</addtitle><date>2009-03-01</date><risdate>2009</risdate><volume>29</volume><issue>5</issue><spage>525</spage><epage>534</epage><pages>525-534</pages><issn>0172-8172</issn><eissn>1437-160X</eissn><abstract>The two major aggrecanases involved in osteoarthritis (OA) are ADAMTS-4 and ADAMTS-5. Knock-out studies suggested that ADAMTS-5, but not ADAMTS-4, is the major aggrecanase in murine OA. However, studies of human articular cartilage suggest that ADAMTS-4 also contributes to aggrecan degradation in human OA. This study investigated ADAMTS-4 in human OA. While ADAMTS-4 was virtually absent in control cartilage, numerous ADAMTS-4 immuno-positive chondrocytes were present in OA cartilage and their numbers increased with disease severity. RT-PCR confirmed expression, especially in the surface zone. DNA methylation was lost at specific CpG sites in the ADAMTS-4 promoter in OA chondrocytes, suggesting that the increased gene expression was more than a simple up-regulation, but involved loss of DNA methylation at specific CpG sites, resulting in a heritable and permanent expression of ADAMTS-4 in OA chondrocytes. These results suggest that ADAMTS-4 is epigenetically regulated and plays a role in aggrecan degradation in human OA.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>18941754</pmid><doi>10.1007/s00296-008-0744-z</doi><tpages>10</tpages></addata></record> |
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| subjects | ADAM Proteins - genetics ADAM Proteins - metabolism ADAMTS4 Protein Aged Aged, 80 and over Cartilage Cartilage (articular) Cartilage, Articular - metabolism Chondrocytes - metabolism Chondrocytes - pathology Deoxyribonucleic acid DNA DNA Methylation Epigenesis, Genetic Female Fluorescent Antibody Technique, Indirect Gene Expression Regulation, Enzymologic Humans Immunohistochemistry Male Medicine Medicine & Public Health Original Article Osteoarthritis - genetics Osteoarthritis - metabolism Procollagen N-Endopeptidase - genetics Procollagen N-Endopeptidase - metabolism Rheumatology |
| title | Expression of ADAMTS-4 by chondrocytes in the surface zone of human osteoarthritic cartilage is regulated by epigenetic DNA de-methylation |
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