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2 results on '"Bardoel, A.F.J."'

1. 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., and TNO Preventie en Gezondheid

Subjects
Biomedical Research, DNA, Complementary, Unclassified drug, Genotype, Clinical article, DNA Mutational Analysis, Molecular Sequence Data, Mutation, Missense, Hydroxylation, Bone and Bones, Enzyme analysis, Telopeptides, Animals, Humans, Amino Acid Sequence, RNA, Messenger, Biology, Genetic disorder, Skin, Tissue, Scleroderma, Systemic, Telopeptide lysyl hydroxylase, Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase, Reverse Transcriptase Polymerase Chain Reaction, Messenger RNA, Linkage (Genetics), Exons, Syndrome, Fibroblasts, Complementary DNA, Fibrosis, Enzymes, Polymerase chain reaction, Procollagen lysine 2 oxoglutarate 5 dioxygenase, Fibrogenesis, Fibroblast culture, Cross-Linking Reagents, Human cell, Mutation, RNA, Systemic sclerosis, Osteogenesis imperfecta, Collagen, Peptides, Nucleotide sequence
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

Published
2003

2. Defective collagen crosslinking in bone, but not in ligament or cartilage, in bruck syndrome: Indications for a bone-specific telopeptide lysyl hydroxylase on chromosome 17

Author

Bank, R.A., Robins, S.P., Wijmenga, C., Breslau-Siderius, L.J., Bardoel, A.F.J., Sluijs, H.A. van der, Pruijs, H.E.H., and Tekoppele, J.M.

Subjects
Genetic Markers, Male, cross linking, Health Biology, Biomedical Research, Contracture, Adolescent, Genotype, joint contracture, macromolecular substances, osteogenesis imperfecta, tissue specificity, Bone and Bones, Collagen Type I, hydroxylation, Consanguinity, Humans, articular cartilage, mineralization, human, Child, collagen synthesis, Growth Disorders, Ligaments, Genome, Human, Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase, Homozygote, article, mechanical stress, Chromosome Mapping, chromosome 17, Syndrome, osteoporosis, peptide, human tissue, procollagen lysine 2 oxoglutarate 5 dioxygenase, Pedigree, short stature, priority journal, scar formation, Child, Preschool, Female, enzyme regulation, Collagen, Bone Diseases, Peptides, Chromosomes, Human, Pair 17
Abstract

Bruck syndrome is characterized by the presence of osteoporosis, joint contractures, fragile bones, and short stature. We report that lysine residues within the telopeptides of collagen type I in bone are underhydroxylated, leading to aberrant crosslinking, but that the lysine residues in the triple helix are normally modified. In contrast to bone, cartilage and ligament show unaltered telopeptide hydroxylation as evidenced by normal patterns of crosslinking. The results provide compelling evidence that collagen crosslinking is regulated primarily by tissue-specific enzymes that hydroxylate only telopeptide lysine residues and not those destined for the helical portion of the molecule. This new family of enzymes appears to provide the primary regulation for controlling the different pathways of collagen crosslinking and explains why crosslink patterns are tissue specific and not related to a genetic collagen type. A genome screen identified only a single region on chromosome 17p12 where all affected sibs shared a cluster of haplotypes identical by descent; this might be the BS (Bruck syndrome) locus and consequently the region where bone telopeptidyl lysyl hydroxylase is located. Further knowledge of this enzyme has important implications for conditions where aberrant expression of telopeptide lysyl hydroxylase occurs, such as fibrosis and scar formation.

Published
1999

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