4-Phenylbutyric acid enhances the mineralization of osteogenesis imperfecta iPSC-derived osteoblasts.
Calcification, Physiologic
/ drug effects
Cell Differentiation
Child, Preschool
Collagen Type I
/ biosynthesis
Endoplasmic Reticulum
/ metabolism
Fibroblasts
/ metabolism
Humans
Induced Pluripotent Stem Cells
/ drug effects
Mutation
Osteoblasts
/ cytology
Osteogenesis Imperfecta
/ metabolism
Phenylbutyrates
/ pharmacology
Protein Folding
endoplasmic reticulum (ER)
extracellular matrix
fibril
glycosylation
osteoblast
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
Historique:
received:
06
06
2020
revised:
26
10
2020
accepted:
05
11
2020
pubmed:
7
11
2020
medline:
28
8
2021
entrez:
6
11
2020
Statut:
ppublish
Résumé
Osteogenesis imperfecta (OI) is a heritable brittle bone disease mainly caused by mutations in the two type I collagen genes. Collagen synthesis is a complex process including trimer formation, glycosylation, secretion, extracellular matrix (ECM) formation, and mineralization. Using OI patient-derived fibroblasts and induced pluripotent stem cells (iPSCs), we investigated the effect of 4-phenylbutyric acid (4-PBA) on collagen synthesis to test its potential as a new treatment for OI. Endoplasmic reticulum (ER) retention of type I collagen was observed by immunofluorescence staining in OI patient-derived fibroblasts with glycine substitution and exon skipping mutations. Liquid chromatography-mass spectrometry analysis revealed excessive glycosylation of secreted type I collagen at the specific sites in OI cells. The misfolding of the type I collagen triple helix in the ECM was demonstrated by the incorporation of heat-dissociated collagen hybridizing peptide in OI cells. Type I collagen was produced excessively by OI fibroblasts with a glycine mutation, but this excessive production was normalized when OI fibroblasts were cultured on control fibroblast-derived ECM. We also found that mineralization was impaired in osteoblasts differentiated from OI iPSCs. In summary, treatment with 4-PBA normalizes the excessive production of type I collagen, reduces ER retention, partially improves misfolding of the type I collagen helix in ECM, and improves osteoblast mineralization. Thus, 4-PBA may improve not only ER retention, but also type I collagen synthesis and mineralization in human cells from OI patients.
Identifiants
pubmed: 33154166
pii: S0021-9258(20)00013-7
doi: 10.1074/jbc.RA120.014709
pmc: PMC7948972
pii:
doi:
Substances chimiques
Collagen Type I
0
Phenylbutyrates
0
4-phenylbutyric acid
7WY7YBI87E
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100027Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
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