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

Autor: Eric Haÿ, Martine Cohen-Solal, Silvia Lecci, Andrea Superti-Furga, Luca Monti, Fabio De Leonardis, Antonio Rossi, Antonella Forlino, Simona Villani, Ruggero Tenni, Chiara Paganini
Rok vydání: 2015
Předmět:
Male
medicine.medical_specialty
Dwarfism
Biology
SLC26A2
Antioxidants
Bone and Bones
Chondrocyte
Mice
Chondrocytes
Sulfation
Pregnancy
In vivo
Internal medicine
Genetics
medicine
Extracellular
Animals
Humans
Molecular Biology
Genetics (clinical)
Cell Proliferation
Acetylcysteine/administration & dosage
Acetylcysteine/pharmacology
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
Proteoglycans/metabolism
Cartilage
General Medicine
Embryo
Mammalian
Acetylcysteine
medicine.anatomical_structure
Endocrinology
Proteoglycan
biology.protein
Proteoglycans
Diastrophic dysplasia
Growth and Development
medicine.symptom
Zdroj: Human Molecular Genetics, vol. 24, no. 19, pp. 5570-5580
ISSN: 1460-2083
0964-6906
DOI: 10.1093/hmg/ddv289
Popis: 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.
Databáze: OpenAIRE
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