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Molecular Consequences of the SERPINH1/HSP47 Mutation in the Dachshund Natural Model of Osteogenesis Imperfecta.

  • Lindert U From the Division of Metabolism, Connective Tissue Unit, University Children's Hospital Zurich, Children's Research Center, 8032 Zurich, Switzerland.
  • Weis MA the Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington 98195.
  • Rai J the Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington 98195.
  • Seeliger F AstraZeneca, Drug Safety and Metabolism, 431 83 Mölndal, Sweden.
  • Hausser I the Institute of Pathology, University Hospital Heidelberg and Electron Microscopy Core Facility, Heidelberg University, 69120 Heidelberg, Germany, and.
  • Leeb T the Institute of Genetics, Vetsuisse Faculty, University of Bern, CH-3001 Bern, Switzerland.
  • Eyre D the Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington 98195.
  • Rohrbach M From the Division of Metabolism, Connective Tissue Unit, University Children's Hospital Zurich, Children's Research Center, 8032 Zurich, Switzerland.
  • Giunta C From the Division of Metabolism, Connective Tissue Unit, University Children's Hospital Zurich, Children's Research Center, 8032 Zurich, Switzerland, Cecilia.Giunta@kispi.uzh.ch.
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  • 2015-05-26
Published in:
  • The Journal of biological chemistry. - 2015
SERPINH1
bone
collagen
connective tissue
cross-links
endoplasmic reticulum stress (ER stress)
extracellular matrix
heat shock protein 47
osteogenesis
Animals
Bone and Bones
Cells, Cultured
Collagen Type I
Disease Models, Animal
Dogs
Endoplasmic Reticulum Stress
Fibroblasts
HSP47 Heat-Shock Proteins
Osteogenesis Imperfecta
Point Mutation
Protein Processing, Post-Translational
Protein Stability
English Osteogenesis imperfecta (OI) is a heritable connective tissue disease characterized by bone fragility and increased risk of fractures. Up to now, mutations in at least 18 genes have been associated with dominant and recessive forms of OI that affect the production or post-translational processing of procollagen or alter bone homeostasis. Among those, SERPINH1 encoding heat shock protein 47 (HSP47), a chaperone exclusive for collagen folding in the ER, was identified to cause a severe form of OI in dachshunds (L326P) as well as in humans (one single case with a L78P mutation). To elucidate the disease mechanism underlying OI in the dog model, we applied a range of biochemical assays to mutant and control skin fibroblasts as well as on bone samples. These experiments revealed that type I collagen synthesized by mutant cells had decreased electrophoretic mobility. Procollagen was retained intracellularly with concomitant dilation of ER cisternae and activation of the ER stress response markers GRP78 and phospho-eIF2α, thus suggesting a defect in procollagen processing. In line with the migration shift detected on SDS-PAGE of cell culture collagen, extracts of bone collagen from the OI dog showed a similar mobility shift, and on tandem mass spectrometry, the chains were post-translationally overmodified. The bone collagen had a higher content of pyridinoline than control dog bone. We conclude that the SERPINH1 mutation in this naturally occurring model of OI impairs how HSP47 acts as a chaperone in the ER. This results in abnormal post-translational modification and cross-linking of the bone collagen.
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  • English
Open access status
bronze
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https://sonar.ch/global/documents/278524
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