ECTS2016 Poster Presentations Paediatric bone disease (14 abstracts)
Loss of type I collagen telopeptide lysyl hydroxylation causes musculoskeletal abnormalities in a zebrafish model of Bruck syndrome
Andy Willaert 1 , Charlotte Ghistelinck 1 , P Eckhard Witten 2 , Ann Huysseune 2 , Pascal Simoens 1 , Sofie Symoens 1 , Fransiska Malfait 1 , Amelie De Muynck 3 , Anne De Paepe 1 , Ronald Y Kwon 4 , Mary Ann Weiss 4 , David E Eyre 4 & Paul Coucke 1
1Center for Medical Genetics, Ghent University, Ghent, Belgium; 2Biology Department, Ghent University, Ghent, Belgium; 3UGCT, Department of Physics and Astronomy, Ghent University, Ghent, Belgium; 4Department of Orthopaedics and Sports Medicine, University of Washington, Seatlle, WA, USA.
Bruck syndrome, a disorder caused by bi-allelic mutations in either PLOD2 or FKBP10, is characterized by flexion contractures and bone fractures and shows strong clinical overlap with the brittle bone disease Osteogenesis Imperfecta. PLOD2 encodes the Lysyl hydroxylase 2 (LH2) enzyme, which is responsible for the hydroxylation of lysine residues in the type-I collagen telopeptides. This hydroxylation directs cross-linking of the collagen fibrils in the extracellular matrix, which is necessary to provide stability and tensile properties to the collagen fibrils. To further elucidate the function of LH2 in vertebrate skeletal development, we studied a zebrafish model, harboring a homozygous plod2 nonsense mutation (permit ECD15/68).
Adult plod2 mutants presented with a shortened body axis and malformed craniofacial structures. μCT scanning showed severe skeletal abnormalities with evidence of bone fragility and fractures. The vertebral column of plod2 mutants was scoliotic with compressed vertebrae and excessive periosteal bone formation at the vertebral end plates. Furthermore, tissue mineral density (TMD) was shown to be increased in the vertebral centra of the mutants. Near the horizontal myoseptum, the muscle fibers have a reduced diameter and the endomysium, a layer of connective tissue ensheathing the individual muscle fibers, was enlarged in mutant fish. Transmission electron microscopy showed a disturbed organization and altered diameter of type I collagen fibrils in mutant vertebral bone. Reduced telopeptide hydroxylation and cross-linking of type I bone collagen was demonstrated in plod2 mutants proving the dysfunctionality of lh2 in these mutant fish.
In conclusion, plod2 mutant zebrafish display reduced type I collagen telopeptide lysyl hydroxylation and cross-linking and disturbed type I collagen fibril formation. The musculoskeletal abnormalities observed in these mutants are concordant with the clinical findings detected in Bruck Syndrome patients. Therefore, the plod2 zebrafish mutant is a promising model for elucidation of the underlying pathogenetic mechanisms leading to Bruck Syndrome.
Article tools
My recent searches
My recently viewed abstracts
Authors
Bone Abstracts
ISSN 2052-1219 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more