Increased Pyridinoline Cross‐Link Levels in Fibrosis is Accomplished by TGFβ Induced Lysyl Hydroxylases 2B Expression
Identifieur interne : 008340 ( Main/Exploration ); précédent : 008339; suivant : 008341Increased Pyridinoline Cross‐Link Levels in Fibrosis is Accomplished by TGFβ Induced Lysyl Hydroxylases 2B Expression
Auteurs : Aj Van Der Slot [Pays-Bas] ; Am Zuurmond [Pays-Bas] ; Ra Bank [Pays-Bas]Source :
- 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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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><affiliations><list><country><li>Pays-Bas</li></country><region><li>Hollande-Méridionale</li></region><settlement><li>Leyde</li></settlement></list><tree><country name="Pays-Bas"><region name="Hollande-Méridionale"><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></region><name sortKey="Bank, Ra" sort="Bank, Ra" uniqKey="Bank R" first="Ra" last="Bank">Ra Bank</name><name sortKey="Zuurmond, Am" sort="Zuurmond, Am" uniqKey="Zuurmond A" first="Am" last="Zuurmond">Am Zuurmond</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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