Increased Pyridinoline Cross‐Link Levels in Fibrosis is Accomplished by TGFβ Induced Lysyl Hydroxylases 2B Expression
Identifieur interne : 007098 ( Istex/Corpus ); précédent : 007097; suivant : 007099Increased Pyridinoline Cross‐Link Levels in Fibrosis is Accomplished by TGFβ Induced Lysyl Hydroxylases 2B Expression
Auteurs : Aj Van Der Slot ; Am Zuurmond ; Ra BankSource :
- Wound Repair and Regeneration [ 1067-1927 ] ; 2005-01.
Abstract
Fibrosis is a complex process involving an acute inflammatory response, which finally results in the excessive deposition of collagen. The deposited collagen shows an increase in pyridinoline cross‐links, due to overhydroxylation of lysine residues within the telopeptides. As we have found that the enzyme responsible for the hydroxylation of the telopeptide lysine residues is lysyl hydroxylase 2 (LH2)[1], it was examined whether LH2 expression is increased in fibrotic lesions. Furthermore, we examined whether the expression of LH2 can be induced by TGFβ, a cytokine playing an important role in fibrotic processes. LH2a and LH2b (two splice variants of LH2) mRNA expression was analyzed in fibroblasts isolated from keloid, hypertrophic scars, fibrotic lesions of Dupuytren's and systemic sclerosis patients, as well as in activated stellate cells, which are responsible for liver fibrosis. Furthermore, LH2b expression was examined in control fibroblasts stimulated with TGFβ1, TGFβ2 and TGFβ3. The matrices deposited by the fibrotic fibroblasts as well as by the TGFβ stimulated control fibroblasts were analyzed for the presence of pyridinoline cross‐links. All fibrotic fibroblasts evaluated showed increased LH2b mRNA expression, which was associated with elevated pyridinoline cross‐link levels in the extracellular matrices deposited by these fibroblasts. LH2a was hardly detectable in all cells, suggesting that this splice variant does not play a significant role in fibrotic conditions. These data indicate that in fibrotic lesions, LH2b is responsible for the overhydroxylation of the collagen telopeptides. TGFβ1, TGFβ2 and TGFβ3 were able to induce LH2b expression. In addition, the three TGFβ isoforms increased the pyridinoline cross‐link levels in the matrices deposited by the stimulated cells, showing that TGFβ promotes the formation of pyridinoline cross‐links via the induction of LH2b expression. We conclude that LH2b plays a key role in fibrotic processes via the formation of pyridinoline cross‐links, giving rise to collagen that is difficult to degrade and therefore significantly contributes to the collagen accumulation.
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DOI: 10.1111/j.1067-1927.2005.130117ad.x
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Increased Pyridinoline Cross‐Link Levels in Fibrosis is Accomplished by TGFβ Induced Lysyl Hydroxylases 2B Expression</title><author><name sortKey="Van Der Slot, Aj" sort="Van Der Slot, Aj" uniqKey="Van Der Slot A" first="Aj" last="Van Der Slot">Aj Van Der Slot</name><affiliation><mods:affiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Zuurmond, Am" sort="Zuurmond, Am" uniqKey="Zuurmond A" first="Am" last="Zuurmond">Am Zuurmond</name><affiliation><mods:affiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Bank, Ra" sort="Bank, Ra" uniqKey="Bank R" first="Ra" last="Bank">Ra Bank</name><affiliation><mods:affiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:F0E17A8D17556E53A65B0F76DF9B55D1064919E9</idno><date when="2005" year="2005">2005</date><idno type="doi">10.1111/j.1067-1927.2005.130117ad.x</idno><idno type="url">https://api.istex.fr/document/F0E17A8D17556E53A65B0F76DF9B55D1064919E9/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">007098</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">007098</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">Increased Pyridinoline Cross‐Link Levels in Fibrosis is Accomplished by TGFβ Induced Lysyl Hydroxylases 2B Expression</title><author><name sortKey="Van Der Slot, Aj" sort="Van Der Slot, Aj" uniqKey="Van Der Slot A" first="Aj" last="Van Der Slot">Aj Van Der Slot</name><affiliation><mods:affiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Zuurmond, Am" sort="Zuurmond, Am" uniqKey="Zuurmond A" first="Am" last="Zuurmond">Am Zuurmond</name><affiliation><mods:affiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Bank, Ra" sort="Bank, Ra" uniqKey="Bank R" first="Ra" last="Bank">Ra Bank</name><affiliation><mods:affiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Wound Repair and Regeneration</title><title level="j" type="alt">WOUND REPAIR REGENERATION</title><idno type="ISSN">1067-1927</idno><idno type="eISSN">1524-475X</idno><imprint><biblScope unit="vol">13</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="A24">A24</biblScope><biblScope unit="page" to="A24">A24</biblScope><biblScope unit="page-count">1</biblScope><publisher>Blackwell Science Inc</publisher><pubPlace>Oxford, UK; Malden, USA</pubPlace><date type="published" when="2005-01">2005-01</date></imprint><idno type="ISSN">1067-1927</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1067-1927</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Fibrosis is a complex process involving an acute inflammatory response, which finally results in the excessive deposition of collagen. The deposited collagen shows an increase in pyridinoline cross‐links, due to overhydroxylation of lysine residues within the telopeptides. As we have found that the enzyme responsible for the hydroxylation of the telopeptide lysine residues is lysyl hydroxylase 2 (LH2)[1], it was examined whether LH2 expression is increased in fibrotic lesions. Furthermore, we examined whether the expression of LH2 can be induced by TGFβ, a cytokine playing an important role in fibrotic processes. LH2a and LH2b (two splice variants of LH2) mRNA expression was analyzed in fibroblasts isolated from keloid, hypertrophic scars, fibrotic lesions of Dupuytren's and systemic sclerosis patients, as well as in activated stellate cells, which are responsible for liver fibrosis. Furthermore, LH2b expression was examined in control fibroblasts stimulated with TGFβ1, TGFβ2 and TGFβ3. The matrices deposited by the fibrotic fibroblasts as well as by the TGFβ stimulated control fibroblasts were analyzed for the presence of pyridinoline cross‐links. All fibrotic fibroblasts evaluated showed increased LH2b mRNA expression, which was associated with elevated pyridinoline cross‐link levels in the extracellular matrices deposited by these fibroblasts. LH2a was hardly detectable in all cells, suggesting that this splice variant does not play a significant role in fibrotic conditions. These data indicate that in fibrotic lesions, LH2b is responsible for the overhydroxylation of the collagen telopeptides. TGFβ1, TGFβ2 and TGFβ3 were able to induce LH2b expression. In addition, the three TGFβ isoforms increased the pyridinoline cross‐link levels in the matrices deposited by the stimulated cells, showing that TGFβ promotes the formation of pyridinoline cross‐links via the induction of LH2b expression. We conclude that LH2b plays a key role in fibrotic processes via the formation of pyridinoline cross‐links, giving rise to collagen that is difficult to degrade and therefore significantly contributes to the collagen accumulation.</div></front></TEI><istex><corpusName>wiley</corpusName><keywords><teeft><json:string>fibroblast</json:string><json:string>myofibroblasts</json:string><json:string>actin</json:string><json:string>matrix</json:string><json:string>myofibroblast</json:string><json:string>extracellular</json:string><json:string>asma</json:string><json:string>apoptosis</json:string><json:string>fibrotic</json:string><json:string>tgfb1</json:string><json:string>stress fibers</json:string><json:string>suture</json:string><json:string>hepatocytes</json:string><json:string>icgn</json:string><json:string>thrombin</json:string><json:string>dermal</json:string><json:string>phenotype</json:string><json:string>extracellular 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Netherlands</json:string></affiliations></json:item></author><articleId><json:string>WRR130117AD</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>abstract</json:string></originalGenre><abstract>Fibrosis is a complex process involving an acute inflammatory response, which finally results in the excessive deposition of collagen. The deposited collagen shows an increase in pyridinoline cross‐links, due to overhydroxylation of lysine residues within the telopeptides. As we have found that the enzyme responsible for the hydroxylation of the telopeptide lysine residues is lysyl hydroxylase 2 (LH2)[1], it was examined whether LH2 expression is increased in fibrotic lesions. Furthermore, we examined whether the expression of LH2 can be induced by TGFβ, a cytokine playing an important role in fibrotic processes. LH2a and LH2b (two splice variants of LH2) mRNA expression was analyzed in fibroblasts isolated from keloid, hypertrophic scars, fibrotic lesions of Dupuytren's and systemic sclerosis patients, as well as in activated stellate cells, which are responsible for liver fibrosis. Furthermore, LH2b expression was examined in control fibroblasts stimulated with TGFβ1, TGFβ2 and TGFβ3. The matrices deposited by the fibrotic fibroblasts as well as by the TGFβ stimulated control fibroblasts were analyzed for the presence of pyridinoline cross‐links. All fibrotic fibroblasts evaluated showed increased LH2b mRNA expression, which was associated with elevated pyridinoline cross‐link levels in the extracellular matrices deposited by these fibroblasts. LH2a was hardly detectable in all cells, suggesting that this splice variant does not play a significant role in fibrotic conditions. These data indicate that in fibrotic lesions, LH2b is responsible for the overhydroxylation of the collagen telopeptides. TGFβ1, TGFβ2 and TGFβ3 were able to induce LH2b expression. In addition, the three TGFβ isoforms increased the pyridinoline cross‐link levels in the matrices deposited by the stimulated cells, showing that TGFβ promotes the formation of pyridinoline cross‐links via the induction of LH2b expression. We conclude that LH2b plays a key role in fibrotic processes via the formation of pyridinoline cross‐links, giving rise to collagen that is difficult to degrade and therefore significantly contributes to the collagen accumulation.</abstract><qualityIndicators><score>8.5</score><pdfVersion>1.4</pdfVersion><pdfPageSize>595 x 782 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>2155</abstractCharCount><pdfWordCount>8613</pdfWordCount><pdfCharCount>55105</pdfCharCount><pdfPageCount>8</pdfPageCount><abstractWordCount>310</abstractWordCount></qualityIndicators><title>Increased Pyridinoline Cross‐Link Levels in Fibrosis is Accomplished by TGFβ Induced Lysyl Hydroxylases 2B Expression</title><genre><json:string>abstract</json:string></genre><host><title>Wound Repair and Regeneration</title><language><json:string>unknown</json:string></language><doi><json:string>10.1111/(ISSN)1524-475X</json:string></doi><issn><json:string>1067-1927</json:string></issn><eissn><json:string>1524-475X</json:string></eissn><publisherId><json:string>WRR</json:string></publisherId><volume>13</volume><issue>1</issue><pages><first>A24</first><last>A24</last><total>1</total></pages><genre><json:string>journal</json:string></genre></host><categories><wos><json:string>science</json:string><json:string>surgery</json:string><json:string>medicine, research & experimental</json:string><json:string>dermatology</json:string><json:string>cell biology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>dermatology & venereal diseases</json:string></scienceMetrix><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences medicales</json:string><json:string>dermatologie</json:string></inist></categories><publicationDate>2005</publicationDate><copyrightDate>2005</copyrightDate><doi><json:string>10.1111/j.1067-1927.2005.130117ad.x</json:string></doi><id>F0E17A8D17556E53A65B0F76DF9B55D1064919E9</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/F0E17A8D17556E53A65B0F76DF9B55D1064919E9/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/F0E17A8D17556E53A65B0F76DF9B55D1064919E9/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/F0E17A8D17556E53A65B0F76DF9B55D1064919E9/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main">Increased Pyridinoline Cross‐Link Levels in Fibrosis is Accomplished by TGFβ Induced Lysyl Hydroxylases 2B Expression</title></titleStmt><publicationStmt><publisher>Blackwell Science Inc</publisher><pubPlace>Oxford, UK; Malden, USA</pubPlace><date type="published" when="2005-01"></date></publicationStmt><notesStmt><note type="content-type" subtype="abstract" source="abstract" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-HPN7T1Q2-R">abstract</note><note type="publication-type" subtype="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="abstract"><analytic><title level="a" type="main">Increased Pyridinoline Cross‐Link Levels in Fibrosis is Accomplished by TGFβ Induced Lysyl Hydroxylases 2B Expression</title><author xml:id="author-0000"><persName><forename type="first">AJ</forename><surname>Van Der Slot</surname></persName><affiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands<address><country key="NL"></country></address></affiliation></author><author xml:id="author-0001"><persName><forename type="first">AM</forename><surname>Zuurmond</surname></persName><affiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands<address><country key="NL"></country></address></affiliation></author><author xml:id="author-0002"><persName><forename type="first">RA</forename><surname>Bank</surname></persName><affiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands<address><country key="NL"></country></address></affiliation></author><idno type="istex">F0E17A8D17556E53A65B0F76DF9B55D1064919E9</idno><idno type="DOI">10.1111/j.1067-1927.2005.130117ad.x</idno><idno type="unit">WRR130117AD</idno><idno type="toTypesetVersion">file:WRR.WRR130117AD.pdf</idno></analytic><monogr><title level="j" type="main">Wound Repair and Regeneration</title><title level="j" type="alt">WOUND REPAIR REGENERATION</title><idno type="pISSN">1067-1927</idno><idno type="eISSN">1524-475X</idno><idno type="book-DOI">10.1111/(ISSN)1524-475X</idno><idno type="book-part-DOI">10.1111/wrr.2005.13.issue-1</idno><idno type="product">WRR</idno><idno type="publisherDivision">ST</idno><imprint><biblScope unit="vol">13</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="A24">A24</biblScope><biblScope unit="page" to="A24">A24</biblScope><biblScope unit="page-count">1</biblScope><publisher>Blackwell Science Inc</publisher><pubPlace>Oxford, UK; Malden, USA</pubPlace><date type="published" when="2005-01"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract xml:lang="en" style="main"><p>Fibrosis is a complex process involving an acute inflammatory response, which finally results in the excessive deposition of collagen. The deposited collagen shows an increase in pyridinoline cross‐links, due to overhydroxylation of lysine residues within the telopeptides. As we have found that the enzyme responsible for the hydroxylation of the telopeptide lysine residues is lysyl hydroxylase 2 (LH2)[<ref type="bibr" target="#b1">1</ref>], it was examined whether LH2 expression is increased in fibrotic lesions. Furthermore, we examined whether the expression of LH2 can be induced by TGFβ, a cytokine playing an important role in fibrotic processes. LH2a and LH2b (two splice variants of LH2) mRNA expression was analyzed in fibroblasts isolated from keloid, hypertrophic scars, fibrotic lesions of Dupuytren's and systemic sclerosis patients, as well as in activated stellate cells, which are responsible for liver fibrosis. Furthermore, LH2b expression was examined in control fibroblasts stimulated with TGFβ1, TGFβ2 and TGFβ3. The matrices deposited by the fibrotic fibroblasts as well as by the TGFβ stimulated control fibroblasts were analyzed for the presence of pyridinoline cross‐links. All fibrotic fibroblasts evaluated showed increased LH2b mRNA expression, which was associated with elevated pyridinoline cross‐link levels in the extracellular matrices deposited by these fibroblasts. LH2a was hardly detectable in all cells, suggesting that this splice variant does not play a significant role in fibrotic conditions. These data indicate that in fibrotic lesions, LH2b is responsible for the overhydroxylation of the collagen telopeptides. TGFβ1, TGFβ2 and TGFβ3 were able to induce LH2b expression. In addition, the three TGFβ isoforms increased the pyridinoline cross‐link levels in the matrices deposited by the stimulated cells, showing that TGFβ promotes the formation of pyridinoline cross‐links via the induction of LH2b expression. We conclude that LH2b plays a key role in fibrotic processes via the formation of pyridinoline cross‐links, giving rise to collagen that is difficult to degrade and therefore significantly contributes to the collagen accumulation.</p></abstract><textClass><classCode scheme="tocHeading1">Abstracts ‐ European Tissue Repair Society Focus Meeting</classCode></textClass><langUsage><language ident="EN"></language></langUsage></profileDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/F0E17A8D17556E53A65B0F76DF9B55D1064919E9/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Blackwell Science Inc</publisherName><publisherLoc>Oxford, UK; Malden, USA</publisherLoc></publisherInfo><doi origin="wiley" registered="yes">10.1111/(ISSN)1524-475X</doi><issn type="print">1067-1927</issn><issn type="electronic">1524-475X</issn><idGroup><id type="product" value="WRR"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="WOUND REPAIR REGENERATION">Wound Repair and Regeneration</title></titleGroup></publicationMeta><publicationMeta level="part" position="01101"><doi origin="wiley">10.1111/wrr.2005.13.issue-1</doi><numberingGroup><numbering type="journalVolume" number="13">13</numbering><numbering type="journalIssue" number="1">1</numbering></numberingGroup><coverDate startDate="2005-01">January 2005</coverDate></publicationMeta><publicationMeta level="unit" type="abstract" position="0002400" status="forIssue"><doi origin="wiley">10.1111/j.1067-1927.2005.130117ad.x</doi><idGroup><id type="unit" value="WRR130117AD"></id></idGroup><countGroup><count type="pageTotal" number="1"></count></countGroup><titleGroup><title type="tocHeading1">Abstracts ‐ European Tissue Repair Society Focus Meeting</title></titleGroup><eventGroup><event type="firstOnline" date="2005-01-17"></event><event type="publishedOnlineFinalForm" date="2005-01-17"></event><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:2.3.17 mode:FullText" date="2010-09-08"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-02-10"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-11-04"></event></eventGroup><numberingGroup><numbering type="pageFirst">A24</numbering><numbering type="pageLast">A24</numbering></numberingGroup><linkGroup><link type="toTypesetVersion" href="file:WRR.WRR130117AD.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="0"></count><count type="tableTotal" number="0"></count><count type="formulaTotal" number="0"></count><count type="referenceTotal" number="0"></count><count type="wordTotal" number="4249"></count><count type="linksPubMed" number="0"></count><count type="linksCrossRef" number="0"></count></countGroup><titleGroup><title type="main">Increased Pyridinoline Cross‐Link Levels in Fibrosis is Accomplished by TGFβ Induced Lysyl Hydroxylases 2B Expression</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1"><personName><givenNames>AJ</givenNames><familyName>Van Der Slot</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a1"><personName><givenNames>AM</givenNames><familyName>Zuurmond</familyName></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a1"><personName><givenNames>RA</givenNames><familyName>Bank</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="NL"><unparsedAffiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands</unparsedAffiliation></affiliation></affiliationGroup><abstractGroup><abstract type="main" xml:lang="en"><p>Fibrosis is a complex process involving an acute inflammatory response, which finally results in the excessive deposition of collagen. The deposited collagen shows an increase in pyridinoline cross‐links, due to overhydroxylation of lysine residues within the telopeptides. As we have found that the enzyme responsible for the hydroxylation of the telopeptide lysine residues is lysyl hydroxylase 2 (LH2)[<link href="#b1">1</link>], it was examined whether LH2 expression is increased in fibrotic lesions. Furthermore, we examined whether the expression of LH2 can be induced by TGFβ, a cytokine playing an important role in fibrotic processes. LH2a and LH2b (two splice variants of LH2) mRNA expression was analyzed in fibroblasts isolated from keloid, hypertrophic scars, fibrotic lesions of Dupuytren's and systemic sclerosis patients, as well as in activated stellate cells, which are responsible for liver fibrosis. Furthermore, LH2b expression was examined in control fibroblasts stimulated with TGFβ1, TGFβ2 and TGFβ3. The matrices deposited by the fibrotic fibroblasts as well as by the TGFβ stimulated control fibroblasts were analyzed for the presence of pyridinoline cross‐links. All fibrotic fibroblasts evaluated showed increased LH2b mRNA expression, which was associated with elevated pyridinoline cross‐link levels in the extracellular matrices deposited by these fibroblasts. LH2a was hardly detectable in all cells, suggesting that this splice variant does not play a significant role in fibrotic conditions. These data indicate that in fibrotic lesions, LH2b is responsible for the overhydroxylation of the collagen telopeptides. TGFβ1, TGFβ2 and TGFβ3 were able to induce LH2b expression. In addition, the three TGFβ isoforms increased the pyridinoline cross‐link levels in the matrices deposited by the stimulated cells, showing that TGFβ promotes the formation of pyridinoline cross‐links via the induction of LH2b expression. We conclude that LH2b plays a key role in fibrotic processes via the formation of pyridinoline cross‐links, giving rise to collagen that is difficult to degrade and therefore significantly contributes to the collagen accumulation.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Increased Pyridinoline Cross‐Link Levels in Fibrosis is Accomplished by TGFβ Induced Lysyl Hydroxylases 2B Expression</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Increased Pyridinoline Cross‐Link Levels in Fibrosis is Accomplished by TGFβ Induced Lysyl Hydroxylases 2B Expression</title></titleInfo><name type="personal"><namePart type="given">AJ</namePart><namePart type="family">Van Der Slot</namePart><affiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">AM</namePart><namePart type="family">Zuurmond</namePart><affiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">RA</namePart><namePart type="family">Bank</namePart><affiliation>TNO Prevention and Health, Biomedical Research Division, Leiden, the Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="abstract" displayLabel="abstract"></genre><originInfo><publisher>Blackwell Science Inc</publisher><place><placeTerm type="text">Oxford, UK; Malden, USA</placeTerm></place><dateIssued encoding="w3cdtf">2005-01</dateIssued><copyrightDate encoding="w3cdtf">2005</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="words">4249</extent></physicalDescription><abstract lang="en">Fibrosis is a complex process involving an acute inflammatory response, which finally results in the excessive deposition of collagen. The deposited collagen shows an increase in pyridinoline cross‐links, due to overhydroxylation of lysine residues within the telopeptides. As we have found that the enzyme responsible for the hydroxylation of the telopeptide lysine residues is lysyl hydroxylase 2 (LH2)[1], it was examined whether LH2 expression is increased in fibrotic lesions. Furthermore, we examined whether the expression of LH2 can be induced by TGFβ, a cytokine playing an important role in fibrotic processes. LH2a and LH2b (two splice variants of LH2) mRNA expression was analyzed in fibroblasts isolated from keloid, hypertrophic scars, fibrotic lesions of Dupuytren's and systemic sclerosis patients, as well as in activated stellate cells, which are responsible for liver fibrosis. Furthermore, LH2b expression was examined in control fibroblasts stimulated with TGFβ1, TGFβ2 and TGFβ3. The matrices deposited by the fibrotic fibroblasts as well as by the TGFβ stimulated control fibroblasts were analyzed for the presence of pyridinoline cross‐links. All fibrotic fibroblasts evaluated showed increased LH2b mRNA expression, which was associated with elevated pyridinoline cross‐link levels in the extracellular matrices deposited by these fibroblasts. LH2a was hardly detectable in all cells, suggesting that this splice variant does not play a significant role in fibrotic conditions. These data indicate that in fibrotic lesions, LH2b is responsible for the overhydroxylation of the collagen telopeptides. TGFβ1, TGFβ2 and TGFβ3 were able to induce LH2b expression. In addition, the three TGFβ isoforms increased the pyridinoline cross‐link levels in the matrices deposited by the stimulated cells, showing that TGFβ promotes the formation of pyridinoline cross‐links via the induction of LH2b expression. We conclude that LH2b plays a key role in fibrotic processes via the formation of pyridinoline cross‐links, giving rise to collagen that is difficult to degrade and therefore significantly contributes to the collagen accumulation.</abstract><relatedItem type="host"><titleInfo><title>Wound Repair and Regeneration</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">1067-1927</identifier><identifier type="eISSN">1524-475X</identifier><identifier type="DOI">10.1111/(ISSN)1524-475X</identifier><identifier type="PublisherID">WRR</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>13</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>A24</start><end>A24</end><total>1</total></extent></part></relatedItem><identifier type="istex">F0E17A8D17556E53A65B0F76DF9B55D1064919E9</identifier><identifier type="DOI">10.1111/j.1067-1927.2005.130117ad.x</identifier><identifier type="ArticleID">WRR130117AD</identifier><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Science Inc</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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