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Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis.

Abstract
The hallmark of fibrotic processes is an excessive accumulation of collagen. The deposited collagen shows an increase in pyridinoline cross-links, which are derived from hydroxylated lysine residues within the telopeptides. This change in cross-linking is related to irreversible accumulation of collagen in fibrotic tissues. The increase in pyridinoline cross-links is likely to be the result of increased activity of the enzyme responsible for the hydroxylation of the telopeptides (telopeptide lysyl hydroxylase, or TLH). Although the existence of TLH has been postulated, the gene encoding TLH has not been identified. By analyzing the genetic defect of Bruck syndrome, which is characterized by a pyridinoline deficiency in bone collagen, we found two missense mutations in exon 17 of PLOD2, thereby identifying PLOD2 as a putative TLH gene. Subsequently, we investigated fibroblasts derived from fibrotic skin of systemic sclerosis (SSc) patients and found that PLOD2 mRNA is highly increased indeed. Furthermore, increased pyridinoline cross-link levels were found in the matrix deposited by SSc fibroblasts, demonstrating a clear link between mRNA levels of the putative TLH gene (PLOD2) and the hydroxylation of lysine residues within the telopeptides. These data underscore the significance of PLOD2 in fibrotic processes.
AuthorsAnnemarie J van der Slot, Anne-Marie Zuurmond, Alfons F J Bardoel, Cisca Wijmenga, Hans E H Pruijs, David O Sillence, Jürgen Brinckmann, David J Abraham, Carol M Black, Nicole Verzijl, Jeroen DeGroot, Roeland Hanemaaijer, Johan M TeKoppele, Tom W J Huizinga, Ruud A Bank
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 42 Pg. 40967-72 (Oct 17 2003) ISSN: 0021-9258 [Print] United States
PMID12881513 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cross-Linking Reagents
  • DNA, Complementary
  • Peptides
  • RNA, Messenger
  • Collagen
  • PLOD2 protein, human
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
Topics
  • Amino Acid Sequence
  • Animals
  • Bone and Bones (metabolism)
  • Collagen (metabolism)
  • Cross-Linking Reagents (pharmacology)
  • DNA Mutational Analysis
  • DNA, Complementary (metabolism)
  • Exons
  • Fibroblasts (metabolism)
  • Fibrosis (enzymology)
  • Genetic Linkage
  • Genotype
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Mutation, Missense
  • Peptides (metabolism)
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase (chemistry, genetics)
  • RNA, Messenger (metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Scleroderma, Systemic (metabolism)
  • Syndrome

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