Functional diversity of lysyl hydroxylase 2 in collagen synthesis of human dermal fibroblasts.

Abstract

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.

• Authors: Jiang Wu, Dieter P Reinhardt, Chimedtseren Batmunkh, Werner Lindenmaier, Rosel Kretschmer-Kazemi Far, Holger Notbohm, Nico Hunzelmann, Jürgen Brinckmann
• Journal: Experimental cell research (Exp Cell Res) Vol. 312 Issue 18 Pg. 3485-94 (Nov 01 2006) ISSN: 0014-4827 [Print] United States
• PMID: 16934803 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type I
• FBN1 protein, human
• Fibrillin-1
• Fibrillins
• Fibronectins
• MYC protein, human
• Microfilament Proteins
• Proto-Oncogene Proteins c-myc
• RNA, Messenger
• Procollagen-Proline Dioxygenase
• PLOD2 protein, human
• Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase

Topics

• Adenoviridae (genetics, metabolism)
• Animals
• Cells, Cultured
• Collagen Type I (biosynthesis, genetics)
• Dermis (cytology)
• Fibrillin-1
• Fibrillins
• Fibroblasts (cytology, physiology)
• Fibronectins (genetics, metabolism)
• Fibrosis (metabolism)
• Genetic Vectors (genetics, metabolism)
• Humans
• Microfilament Proteins (genetics, metabolism)
• Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase (genetics, metabolism)
• Procollagen-Proline Dioxygenase (genetics, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• RNA, Messenger (metabolism)