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Hum Mol Genet. 2017 Aug 1;26(15):2897-2911. doi: 10.1093/hmg/ddx171.

The chaperone activity of 4PBA ameliorates the skeletal phenotype of Chihuahua, a zebrafish model for dominant osteogenesis imperfecta.

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Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
Section on Physical Biochemistry, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, USA.
Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
Center for Genome Research, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Institute of Osteology and Biomechanic, Center for Experimental Medicine, University of Hamburg, Hamburg, Germany.
Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Medical Faculty, Center for Biochemistry, Center for Molecular Medicine, University of Cologne, Cologne, Germany.
Department of Public Health and Experimental and Forensic Medicine, Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia, Italy.


Classical osteogenesis imperfecta (OI) is a bone disease caused by type I collagen mutations and characterized by bone fragility, frequent fractures in absence of trauma and growth deficiency. No definitive cure is available for OI and to develop novel drug therapies, taking advantage of a repositioning strategy, the small teleost zebrafish (Danio rerio) is a particularly appealing model. Its small size, high proliferative rate, embryo transparency and small amount of drug required make zebrafish the model of choice for drug screening studies, when a valid disease model is available. We performed a deep characterization of the zebrafish mutant Chihuahua, that carries a G574D (p.G736D) substitution in the α1 chain of type I collagen. We successfully validated it as a model for classical OI. Growth of mutants was delayed compared with WT. X-ray, µCT, alizarin red/alcian blue and calcein staining revealed severe skeletal deformity, presence of fractures and delayed mineralization. Type I collagen extracted from different tissues showed abnormal electrophoretic migration and low melting temperature. The presence of endoplasmic reticulum (ER) enlargement due to mutant collagen retention in osteoblasts and fibroblasts of mutant fish was shown by electron and confocal microscopy. Two chemical chaperones, 4PBA and TUDCA, were used to ameliorate the cellular stress and indeed 4PBA ameliorated bone mineralization in larvae and skeletal deformities in adult, mainly acting on reducing ER cisternae size and favoring collagen secretion. In conclusion, our data demonstrated that ER stress is a novel target to ameliorate OI phenotype; chemical chaperones such as 4PBA may be, alone or in combination, a new class of molecules to be further investigated for OI treatment.

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