Print Email Facebook Twitter Minoxidil exerts different inhibitory effects on gene expression of lysyl hydroxylase 1, 2, and 3: Implications for collagen cross-linking and treatment of fibrosis Title Minoxidil exerts different inhibitory effects on gene expression of lysyl hydroxylase 1, 2, and 3: Implications for collagen cross-linking and treatment of fibrosis Author Zuurmond, A.M. Slot van der-Verhoeven, A.J. van Dura, E.A. de Groot, J. Bank, R.A. TNO Kwaliteit van Leven Publication year 2005 Abstract Collagen deposits in fibrotic lesions often display elevated levels of hydroxyallysine (pyridinoline) cross-links. The relation between the occurrence of pyridinoline cross-links and the irreversibility of fibrosis suggests that these cross-links contribute to the aberrant accumulation of collagen. Based on its inhibitory effect on lysyl hydroxylase activity minoxidil has been postulated to possess anti-fibrotic properties by limiting the hydroxylysine supply for hydroxyallysine cross-linking. However, to interfere with hydroxyallysine cross-linking specifically lysyl hydroxylation of the collagen telopeptide should be inhibited, a reaction predominantly catalysed by lysyl hydroxylase (LH) 2b. In this study, we demonstrate that minoxidil treatment of cultured fibroblasts reduces LH1>>LH2b>LH3 mRNA levels dose-and time-dependently, but has essentially no effect on the total number of pyridinoline cross-links in the collagen matrix. Still the collagen produced in the presence of minoxidil displays some remarkable features: hydroxylation of triple helical lysine residues is reduced to 50% and lysylpyridinoline cross-linking is increased at the expense of hydroxylysylpyridinoline cross-linking. These observations can be explained by our finding that LH1 mRNA levels are the most sensitive to minoxidil treatment, corroborating that LH1 has a preference for triple helical lysine residues as substrate. In addition, the non-proportional increase in cross-links (20-fold) with respect to the decrease in lysyl hydroxylation state of the triple helix (2-fold) even suggests that LH1 preferentially hydroxylates triple helical lysine residues at the cross-link positions. We conclude that minoxidil is unlikely to serve as an anti-fibroticum, but confers features to the collagen matrix, which provide insight into the substrate specificity of LH1. © 2005 Elsevier B.V./International Society of Matrix Biology. All rights reserved. Chemicals / CAS: collagen, 9007-34-5; minoxidil, 38304-91-5; procollagen lysine 2 oxoglutarate 5 dioxygenase, 9059-25-0; pyridinoline, 63800-01-1; 2-Aminoadipic Acid, 542-32-5; Collagen, 9007-34-5; hydroxyallysine, 30382-02-6; lysyl hydroxylase 1, human, EC 126.96.36.199; lysyl hydroxylase 3, human, EC 1.14.11.-; Minoxidil, 38304-91-5; PLOD2 protein, human, EC 188.8.131.52; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase, EC 184.108.40.206 Subject BiologyBiomedical ResearchLysyl hydroxylasePyridinoline cross-linksMessenger RNAProcollagen lysine 2 oxoglutarate 5 dioxygenasePyridinolineConcentration responseControlled studyDose time effect relationDrug activityDrug inhibitionDrug sensitivityEnzyme specificityEnzyme substrateExtracellular matrixFibroblast cultureHuman cellProtein cross linkingProtein structureSkin fibrosis2-Aminoadipic AcidCells, CulturedChromatography, High Pressure LiquidCollagenFibrosisGene Expression Regulation, EnzymologicHumansHydroxylationMinoxidilProcollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase To reference this document use: http://resolver.tudelft.nl/uuid:880d30a2-2c17-4fcc-8484-04279f70d9a2 DOI https://doi.org/10.1016/j.matbio.2005.04.002 TNO identifier 238531 ISSN 0945-053X Source Matrix Biology, 24 (4), 261-270 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.