Improvement of the skeletal phenotype in a mouse model of diastrophic dysplasia after postnatal treatment with N-acetylcysteine.

Abstract

Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by mutations in the SLC26A2 gene encoding for a sulfate/chloride transporter. When SLC26A2 is impaired intracellular level of sulfate is reduced leading to the synthesis of undersulfated proteoglycans. In normal chondrocytes, the main source of intracellular sulfate is the extracellular uptake through SLC26A2, but a small amount comes from the catabolism of sulfur-containing amino acids and other thiols. Here N-acetylcysteine (NAC), an extensively used drug, is proposed as alternative source of intracellular sulfate in an animal model of DTD (dtd mouse). Mutant and wild type mice were treated twice a day with hypodermic injections of 250 mg NAC/kg body weight for one week after birth. At the end of the treatment, an improvement trend in cartilage proteoglycan sulfation and in the skeletal phenotype of treated dtd mice were observed. Thus, a longer treatment lasted three weeks starting from birth was performed. Treated mutant mice showed a significant increase of cartilage proteoglycan sulfation and a relevant improvement of the skeletal phenotype based on measurements of several bony elements and bone quality by DEXA and micro CT. Moreover, the amelioration of the overall growth plate morphology in treated dtd mice suggested a partial rescue of the endochondral ossification process. Overall, the results prove that NAC is an effective source of intracellular sulfate for dtd mice in the postnatal period. This finding paves the way for a potential pharmacological treatment of DTD patients taking advantage from a drug repositioning strategy.

• Authors: Chiara Paganini, Chiara Gramegna Tota, Luca Monti, Ilaria Monti, Antonio Maurizi, Mattia Capulli, Morgane Bourmaud, Anna Teti, Martine Cohen-Solal, Simona Villani, Antonella Forlino, Andrea Superti-Furga, Antonio Rossi
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 185 Pg. 114452 (03 2021) ISSN: 1873-2968 [Electronic] England
• PMID: 33545117 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Free Radical Scavengers
• Acetylcysteine

Topics

• Acetylcysteine (administration & dosage, pharmacokinetics)
• Animals
• Animals, Newborn
• Bone Density (drug effects, physiology)
• Disease Models, Animal
• Dwarfism (diagnostic imaging, drug therapy, metabolism)
• Free Radical Scavengers (administration & dosage, pharmacokinetics)
• Male
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Transgenic
• Phenotype