Universität zu Köln

Gioia, Roberta, Tonelli, Francesca ORCID: 0000-0002-2111-917X, Ceppi, Ilaria, Biggiogera, Marco, Leikin, Sergey ORCID: 0000-0001-7095-0739, Fisher, Shannon, Tenedini, Elena, Yorgan, Timur A., Schinke, Thorsten, Tian, Kun, Schwartz, Jean-Marc ORCID: 0000-0002-6472-0184, Forte, Fabiana, Wagener, Raimund, Villani, Simona, Rossi, Antonio and Forlino, Antonella (2017). The chaperone activity of 4PBA ameliorates the skeletal phenotype of Chihuahua, a zebrafish model for dominant osteogenesis imperfecta. Hum. Mol. Genet., 26 (15). S. 2897 - 2912. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

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 alpha 1 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, mCT, 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gioia, Roberta UNSPECIFIED UNSPECIFIED UNSPECIFIED Tonelli, Francesca UNSPECIFIED orcid.org/0000-0002-2111-917X UNSPECIFIED Ceppi, Ilaria UNSPECIFIED UNSPECIFIED UNSPECIFIED Biggiogera, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Leikin, Sergey UNSPECIFIED orcid.org/0000-0001-7095-0739 UNSPECIFIED Fisher, Shannon UNSPECIFIED UNSPECIFIED UNSPECIFIED Tenedini, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Yorgan, Timur A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schinke, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Tian, Kun UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwartz, Jean-Marc UNSPECIFIED orcid.org/0000-0002-6472-0184 UNSPECIFIED Forte, Fabiana UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagener, Raimund UNSPECIFIED UNSPECIFIED UNSPECIFIED Villani, Simona UNSPECIFIED UNSPECIFIED UNSPECIFIED Rossi, Antonio UNSPECIFIED UNSPECIFIED UNSPECIFIED Forlino, Antonella UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-224387
DOI:	10.1093/hmg/ddx171
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	26
Number:	15
Page Range:	S. 2897 - 2912
Date:	2017
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ENDOPLASMIC-RETICULUM STRESS; IV MOUSE MODEL; IN-VIVO; MURINE MODEL; OSTEOBLAST DIFFERENTIATION; MISFOLDED PROCOLLAGEN; ER STRESS; COLLAGEN; BONE; MICE Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22438