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

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The chaperone activity of 4PBA ameliorates the skeletal phenotype of Chihuahua, a zebrafish model for dominant osteogenesis imperfecta. / Gioia, Roberta; Tonelli, Francesca; Ceppi, Ilaria; Biggiogera, Marco; Leikin, Sergey; Fisher, Shannon; Tenedini, Elena; Yorgan, Timur A; Schinke, Thorsten; Tian, Kun; Schwartz, Jean-Marc; Forte, Fabiana; Wagener, Raimund; Villani, Simona; Rossi, Antonio; Forlino, Antonella.

In: HUM MOL GENET, Vol. 26, No. 15, 01.08.2017, p. 2897-2911.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Gioia, R, Tonelli, F, Ceppi, I, Biggiogera, M, Leikin, S, Fisher, S, Tenedini, E, Yorgan, TA, Schinke, T, Tian, K, Schwartz, J-M, Forte, F, Wagener, R, Villani, S, Rossi, A & Forlino, A 2017, 'The chaperone activity of 4PBA ameliorates the skeletal phenotype of Chihuahua, a zebrafish model for dominant osteogenesis imperfecta', HUM MOL GENET, vol. 26, no. 15, pp. 2897-2911. https://doi.org/10.1093/hmg/ddx171

APA

Gioia, R., Tonelli, F., Ceppi, I., Biggiogera, M., Leikin, S., Fisher, S., Tenedini, E., Yorgan, T. A., Schinke, T., Tian, K., Schwartz, J-M., Forte, F., Wagener, R., Villani, S., Rossi, A., & Forlino, A. (2017). The chaperone activity of 4PBA ameliorates the skeletal phenotype of Chihuahua, a zebrafish model for dominant osteogenesis imperfecta. HUM MOL GENET, 26(15), 2897-2911. https://doi.org/10.1093/hmg/ddx171

Vancouver

Gioia R, Tonelli F, Ceppi I, Biggiogera M, Leikin S, Fisher S et al. The chaperone activity of 4PBA ameliorates the skeletal phenotype of Chihuahua, a zebrafish model for dominant osteogenesis imperfecta. HUM MOL GENET. 2017 Aug 1;26(15):2897-2911. https://doi.org/10.1093/hmg/ddx171

Bibtex

@article{599e591652b84fcc8ceac265bb342072,
title = "The chaperone activity of 4PBA ameliorates the skeletal phenotype of Chihuahua, a zebrafish model for dominant osteogenesis imperfecta",
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 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.",
keywords = "Journal Article",
author = "Roberta Gioia and Francesca Tonelli and Ilaria Ceppi and Marco Biggiogera and Sergey Leikin and Shannon Fisher and Elena Tenedini and Yorgan, {Timur A} and Thorsten Schinke and Kun Tian and Jean-Marc Schwartz and Fabiana Forte and Raimund Wagener and Simona Villani and Antonio Rossi and Antonella Forlino",
note = "{\textcopyright} The Author 2017. Published by Oxford University Press.",
year = "2017",
month = aug,
day = "1",
doi = "10.1093/hmg/ddx171",
language = "English",
volume = "26",
pages = "2897--2911",
journal = "HUM MOL GENET",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "15",

}

RIS

TY - JOUR

T1 - The chaperone activity of 4PBA ameliorates the skeletal phenotype of Chihuahua, a zebrafish model for dominant osteogenesis imperfecta

AU - Gioia, Roberta

AU - Tonelli, Francesca

AU - Ceppi, Ilaria

AU - Biggiogera, Marco

AU - Leikin, Sergey

AU - Fisher, Shannon

AU - Tenedini, Elena

AU - Yorgan, Timur A

AU - Schinke, Thorsten

AU - Tian, Kun

AU - Schwartz, Jean-Marc

AU - Forte, Fabiana

AU - Wagener, Raimund

AU - Villani, Simona

AU - Rossi, Antonio

AU - Forlino, Antonella

N1 - © The Author 2017. Published by Oxford University Press.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1093/hmg/ddx171

DO - 10.1093/hmg/ddx171

M3 - SCORING: Journal article

C2 - 28475764

VL - 26

SP - 2897

EP - 2911

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 15

ER -