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Identification of PLOD2 as Telopeptide Lysyl Hydroxylase, an Important Enzyme in Fibrosis

Author: Slot, A.J. van der · 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. · Groot, J. de · Hanemaaijer, R. · Koppele, J.M. te · Huizinga, T.W.J. · Bank, R.A.
Type:article
Date:2003
Institution: TNO Preventie en Gezondheid
Source:Journal of Biological Chemistry, 42, 278, 40967-40972
Identifier: 237328
doi: doi:10.1074/jbc.M307380200
Keywords: Biology · 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

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