From Cysteamine to Pepstatin A: Targeting Cathepsin D To Improve Bone Health in Cystinosis.

Nephropathic cystinosis is a rare genetic lysosomal storage disorder caused by loss-of-function variants of the CTNS gene encoding for the lysosomal H+/cystine symporter cystinosin. The lack of cystinosin causes cystine accumulation in lysosomes and cell damage. Children with nephropathic cystinosis commonly exhibit skeletal abnormalities, including growth retardation, osteopenia and rickets. The only cystine-depleting drug available is cysteamine. However, several observations suggest that cysteamine, particularly at high doses, may have negative effects on the skeleton. In this study, we characterized the effects of cysteamine on bone cells and we identified Pepstatin A, a Cathepsin D-inhibitor, as a potential new therapeutic treatment to restore physiological bone remodeling in cystinosis. We observed a detrimental effect of cysteamine on bone cells inducing further impairment of osteoblast differentiation/activity and failure of cysteamine intraperitoneal injection to improve the somatic growth of pre-pubertal ctns-/- mice. Moreover, we demonstrated that Pepstatin A treatment increased bone formation in vitro acting on the Fibronectin/Sipa1/STAT3/JunB pathway, and rescued somatic growth and bone mass in pre-pubertal ctns-/- mice. Our results provide evidence that cysteamine negatively affects bone in cystinosis and that Cathepsin D inhibition could represent a new therapeutic approach for rescue of bone remodeling in cystinosis.