Title
Identification of PLOD2 as Telopeptide Lysyl Hydroxylase, an Important Enzyme in Fibrosis
Author
TNO Preventie en Gezondheid
van der Slot, A.J.
Zuurmond, A.M.
Bardoel, A.F.J.
Wijmenga, C.
Pruijs, H.E.H.
Sillence, D.O.
Brinckmann, J.
Abraham, D.J.
Black, C.M.
Verzijl, N.
de Groot, J.
Hanemaaijer, R.
te Koppele, J.M.
Huizinga, T.W.J.
Bank, R.A.
Publication year
2003
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. Chemicals/CAS: collagen, 9007-34-5; procollagen lysine 2 oxoglutarate 5 dioxygenase, 9059-25-0; Collagen, 9007-34-5; Cross-Linking Reagents; DNA, Complementary; Peptides; PLOD2 protein, human, EC 1.14.11.4; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase, EC 1.14.11.4; RNA, Messenger
Subject
Biomedical Research
Collagen
Hydroxylation
RNA
Skin
Tissue
Telopeptides
Enzymes
Complementary DNA
Messenger RNA
Procollagen lysine 2 oxoglutarate 5 dioxygenase
Telopeptide lysyl hydroxylase
Unclassified drug
Clinical article
Enzyme analysis
Fibroblast culture
Fibrogenesis
Genetic disorder
Genotype
Human cell
Nucleotide sequence
Osteogenesis imperfecta
Polymerase chain reaction
Systemic sclerosis
Amino Acid Sequence
Animals
Bone and Bones
Cross-Linking Reagents
DNA Mutational Analysis
DNA, Complementary
Exons
Fibroblasts
Fibrosis
Genotype
Humans
Linkage (Genetics)
Molecular Sequence Data
Mutation
Mutation, Missense
Peptides
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger
Scleroderma, Systemic
Syndrome
To reference this document use:
http://resolver.tudelft.nl/uuid:eb8984a9-b688-49c9-92d6-eacf8a5f5d96
DOI
https://doi.org/10.1074/jbc.m307380200
TNO identifier
237328
ISSN
0021-9258
Source
Journal of Biological Chemistry, 278 (278), 40967-40972
Document type
article