Loss of Type I Collagen Telopeptide Lysyl Hydroxylation Causes Musculoskeletal Abnormalities in a Zebrafish Model of Bruck Syndrome

Gistelinck, C., Eckhard Witten, P., Huysseune, A., Symoens, S., Malfait, F., Larionova, D., Simoens, P., Dierick, M., Van Hoorebeke, L., De Paepe, A., Kwon, R.Y., Weis, M., Eyre, D.R., Willaert, A., Coucke, P.J.
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research   31(11): 1930-1942 (Journal)
Registered Authors
Coucke, Paul, Huysseune, Ann, Willaert, Andy
Bruck Syndrome, Collagen, Lysyl Hydroxylase 2, Osteogenesis Imperfecta, Plod2
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Arthrogryposis/complications
  • Arthrogryposis/diagnostic imaging
  • Arthrogryposis/metabolism
  • Arthrogryposis/pathology*
  • Bone and Bones/abnormalities
  • Bone and Bones/diagnostic imaging
  • Bone and Bones/pathology
  • Calcification, Physiologic
  • Catalytic Domain
  • Codon, Nonsense/genetics
  • Collagen Type I/metabolism*
  • Conserved Sequence/genetics
  • Cross-Linking Reagents/metabolism
  • Evolution, Molecular
  • Hydroxylation
  • Larva/metabolism
  • Lysine/metabolism*
  • Mass Spectrometry
  • Musculoskeletal Abnormalities/complications
  • Musculoskeletal Abnormalities/diagnostic imaging
  • Musculoskeletal Abnormalities/metabolism
  • Musculoskeletal Abnormalities/pathology*
  • Notochord/pathology
  • Osteogenesis Imperfecta/complications
  • Osteogenesis Imperfecta/diagnostic imaging
  • Osteogenesis Imperfecta/metabolism
  • Osteogenesis Imperfecta/pathology*
  • Peptides/metabolism*
  • Phenotype
  • X-Ray Microtomography
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
27541483 Full text @ J. Bone Miner. Res.
Bruck syndrome (BS) is a disorder characterized by joint flexion contractures and skeletal dysplasia that shows strong clinical overlap with the brittle bone disease Osteogenesis Imperfecta (OI). BS is caused by bi-allelic mutations in either the FKBP10 or the PLOD2 gene. PLOD2 encodes the lysyl hydroxylase 2 (LH2) enzyme, which is responsible for the hydroxylation of lysine residues in fibrillar collagen telopeptides. This hydroxylation directs cross-linking of collagen fibrils in the extracellular matrix, which is necessary to provide stability and tensile integrity to the collagen fibrils. To further elucidate the function of LH2 in vertebrate skeletal development, we created a zebrafish model harboring a homozygous plod2 nonsense mutation resulting in reduced telopeptide hydroxylation and cross-linking of bone type I collagen. Adult plod2 mutants present with a shortened body axis and severe skeletal abnormalities with evidence of bone fragility and fractures. The vertebral column of plod2 mutants is short and scoliotic with compressed vertebrae that show excessive bone formation at the vertebral end plates, and increased tissue mineral density in the vertebral centra. The muscle fibers of mutant zebrafish have a reduced diameter near the horizontal myoseptum. The endomysium, a layer of connective tissue ensheathing the individual muscle fibers, is enlarged. Transmission electron microscopy of mutant vertebral bone shows type I collagen fibrils that are less organized with loss of the typical plywood-like structure. In conclusion, plod2 mutant zebrafish show molecular and tissue abnormalities in the musculoskeletal system that are concordant with clinical findings in BS patients. Therefore, the plod2 zebrafish mutant is a promising model for the elucidation of the underlying pathogenetic mechanisms leading to BS and the development of novel therapeutic avenues in this syndrome.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes