title: N-acetylcysteine treatment ameliorates the skeletal phenotype of a mouse model of diastrophic dysplasia.
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.
authors.affiliation: Department of Molecular Medicine, Unit of Biochemistry and.
authors.forename: Luca
authors.initials: L
authors.lastname: Monti
authors.affiliation: Department of Molecular Medicine, Unit of Biochemistry and.
authors.forename: Chiara
authors.initials: C
authors.lastname: Paganini
authors.affiliation: Department of Molecular Medicine, Unit of Biochemistry and.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lecci
authors.affiliation: Department of Molecular Medicine, Unit of Biochemistry and.
authors.forename: Fabio
authors.initials: F
authors.lastname: De Leonardis
authors.affiliation: Inserm U1132 and University Paris 7, Hopital Lariboisiere, 75010 Paris, France and.
authors.forename: Eric
authors.initials: E
authors.lastname: Hay
authors.affiliation: Inserm U1132 and University Paris 7, Hopital Lariboisiere, 75010 Paris, France and.
authors.forename: Martine
authors.initials: M
authors.lastname: Cohen-Solal
authors.affiliation: Department of Public Health, Experimental and Forensic Medicine, Unit of Biostatistics and Clinical Epidemiology, University of Pavia, 27100 Pavia, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Villani
authors.affiliation: Department of Pediatrics, Lausanne University Hospital, University of Lausanne, Lausanne 1011, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.affiliation: Department of Molecular Medicine, Unit of Biochemistry and.
authors.forename: Ruggero
authors.initials: R
authors.lastname: Tenni
authors.affiliation: Department of Molecular Medicine, Unit of Biochemistry and.
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
authors.affiliation: Department of Molecular Medicine, Unit of Biochemistry and antrossi@unipv.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000008:administration & dosage*; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects*; D004195:Disease Models, Animal; D004392:Dwarfism / Q000188:drug therapy* / Q000473:pathology; D004622:Embryo, Mammalian / Q000187:drug effects; D005260:Female; D048788:Growth and Development / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D011247:Pregnancy; D011509:Proteoglycans / Q000378:metabolism
chemical_list: D000975:Antioxidants; D011509:Proteoglycans; D000111:Acetylcysteine