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

Biochem Pharmacol. 2021 Mar;185:114452. doi: 10.1016/j.bcp.2021.114452. Epub 2021 Feb 3.


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.

Keywords: Cartilage; N-acetylcysteine; Proteoglycan; Skeletal dysplasia; Sulfation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Free Radical Scavengers
  • Acetylcysteine

Supplementary concepts

  • Diastrophic dysplasia