N-acetylcysteine treatment ameliorates the skeletal phenotype of a mouse model of diastrophic dysplasia.

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Serval ID
serval:BIB_E41CFFD2210F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
N-acetylcysteine treatment ameliorates the skeletal phenotype of a mouse model of diastrophic dysplasia.
Journal
Human Molecular Genetics
Author(s)
Monti L., Paganini C., Lecci S., De Leonardis F., Hay E., Cohen-Solal M., Villani S., Superti-Furga A., Tenni R., Forlino A., Rossi A.
ISSN
1460-2083 (Electronic)
ISSN-L
0964-6906
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
24
Number
19
Pages
5570-5580
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by mutations in SLC26A2, a cell membrane sulfate-chloride antiporter. Sulfate uptake impairment results in low cytosolic sulfate, leading to cartilage proteoglycan (PG) undersulfation. In this work, we used the dtd mouse model to study the role of N-acetyl-l-cysteine (NAC), a well-known drug with antioxidant properties, as an intracellular sulfate source for macromolecular sulfation. Because of the important pre-natal phase of skeletal development and growth, we administered 30 g/l NAC in the drinking water to pregnant mice to explore a possible transplacental effect on the fetuses. When cartilage PG sulfation was evaluated by high-performance liquid chromatography disaccharide analysis in dtd newborn mice, a marked increase in PG sulfation was observed in newborns from NAC-treated pregnancies when compared with the placebo group. Morphometric studies of the femur, tibia and ilium after skeletal staining with alcian blue and alizarin red indicated a partial rescue of abnormal bone morphology in dtd newborns from treated females, compared with pups from untreated females. The beneficial effect of increased macromolecular sulfation was confirmed by chondrocyte proliferation studies in cryosections of the tibial epiphysis by proliferating cell nuclear antigen immunohistochemistry: the percentage of proliferating cells, significantly reduced in the placebo group, reached normal values in dtd newborns from NAC-treated females. In conclusion, NAC is a useful source of sulfate for macromolecular sulfation in vivo when extracellular sulfate supply is reduced, confirming the potential of therapeutic approaches with thiol compounds to improve skeletal deformity and short stature in human DTD and related disorders.
Keywords
Acetylcysteine/administration & dosage, Acetylcysteine/pharmacology, Animals, Animals, Newborn, Antioxidants/administration & dosage, Bone and Bones/drug effects, Bone and Bones/pathology, Cell Proliferation/drug effects, Chondrocytes/cytology, Chondrocytes/drug effects, Disease Models, Animal, Dwarfism/drug therapy, Dwarfism/pathology, Embryo, Mammalian/drug effects, Female, Growth and Development/drug effects, Humans, Male, Mice, Pregnancy, Proteoglycans/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
17/11/2015 17:32
Last modification date
25/09/2019 6:11
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