Functional diversity of lysyl hydroxylase 2 in collagen synthesis of human dermal fibroblasts.
The pathogenesis of fibrosis, especially involving post-translational modifications of collagen, is poorly understood. Lysyl hydroxylase 2 (long) (LH2 (long)) is thought to play a pivotal role in fibrosis by directing the collagen cross-link pattern. Here we show that LH2 (long) exerts a bimodal function on collagen synthesis in human dermal fibroblasts. Adenoviral-mediated overexpression of LH2 (long) resulted in a mRNA increase of collagen alpha1(I) but not of fibronectin and fibrillin-1. This was accompanied by a higher mRNA level of prolyl-4-hydroxylase but not of other ER proteins (Bip, Hsp47, LH1, LH3). The collagen mRNA increase led to an elevated collagen synthesis, which was higher in the fraction of extracellularly deposited, cell-associated collagen than in the medium. The cross-link pattern of cell-associated collagen showed an increase of the hydroxylysine-aldehyde-derived cross-link dihydroxylysinonorleucine and a decrease of the lysine-aldehyde-derived component hydroxylysinonorleucine. The helical lysyl hydroxylation of the procollagen molecule was unaltered. The increase of collagen synthesis in fibroblasts overexpressing LH2 (long) was independent from cross-linking as it was also observed in the presence of beta-aminopropionitril, a cross-linking inhibitor. Together our data identify LH2 (long) as a bifunctional protein and underscores its potential role in the pathogenesis of fibrosis.
Wu
Jiang
J
Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Reinhardt
Dieter P
DP
Batmunkh
Chimedtseren
C
Lindenmaier
Werner
W
Far
Rosel Kretschmer-Kazemi
RK
Notbohm
Holger
H
Hunzelmann
Nico
N
Brinckmann
Jürgen
J
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D020405:Dermis / Q000166:cytology*; D000071838:Fibrillin-1; D000071837:Fibrillins; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D054392:Adipokines
D024042:Collagen Type I; D000071838:Fibrillin-1; D000071837:Fibrillins; D005353:Fibronectins; D008840:Microfilament Proteins; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D011393:Procollagen-Proline Dioxygenase; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C000605722:FBN1 protein, human; D054392:Adipokines; C489427:MYC protein, human; C479138:PLOD2 protein, human