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

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

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  • NSTL
  • Elsevier
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.

CartilageN-acetylcysteineProteoglycanSkeletal dysplasiaSulfation

Paganini, Chiara、Tota, Chiara Gramegna、Monti, Luca、Monti, Ilaria、Maurizi, Antonio、Capulli, Mattia、Bourmaud, Morgane、Teti, Anna、Cohen-Solal, Martine、Villani, Simona、Forlino, Antonella、Superti-Furga, Andrea、Rossi, Antonio

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Univ Pavia, Dept Mol Med, Unit Biochem, I-27100 Pavia, Italy

Univ Aquila, Dept Biotechnol & Appl Clin Sci, I-67100 Laquila, Italy

Hop Lariboisiere, Bioscar Inserm U1132, F-75010 Paris, France

Univ Pavia, Dept Publ Hlth Expt & Forens Med, Unit Biostat & Clin Epidemiol, I-27100 Pavia, Italy

Lausanne Univ Hosp, Div Genet Med, CH-1011 Lausanne, Switzerland

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2021

10.1016/j.bcp.2021.114452

Biochemical Pharmacology

Biochemical Pharmacology

ISTP
ISSN：0006-2952
年,卷(期)：2021.185
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