Response to Cysteamine in Osteoclasts Obtained from Patients with Nephropathic Cystinosis: A Genotype/Phenotype Correlation.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI
    • Subject Terms:
      Cysteamine/*pharmacology ; Cystinosis/*genetics ; Osteoclasts/*metabolism; Adolescent ; Adult ; Amino Acid Transport Systems, Neutral/genetics ; Amino Acid Transport Systems, Neutral/metabolism ; Cell Differentiation/drug effects ; Child ; Child, Preschool ; Cysteamine/metabolism ; Cystinosis/metabolism ; Cystinosis/physiopathology ; Female ; Genetic Association Studies/methods ; Genotype ; Humans ; Leukocytes, Mononuclear ; Male ; Middle Aged ; Mutation ; Osteoclasts/drug effects ; Phenotype
    • Abstract:
      Bone complications of cystinosis have been recently described. The main objectives of this paper were to determine in vitro the impact of CTNS mutations and cysteamine therapy on human osteoclasts and to carry out a genotype-phenotype analysis related to osteoclastic differentiation. Human osteoclasts were differentiated from peripheral blood mononuclear cells (PBMCs) and were treated with increasing doses of cysteamine (0, 50, 200 µM) and then assessed for osteoclastic differentiation. Results are presented as median (min-max). A total of 17 patients (mainly pediatric) were included, at a median age of 14 (2-61) years, and a eGFR of 64 (23-149) mL/min/1.73 m 2 . Most patients (71%) were under conservative kidney management (CKM). The others were kidney transplant recipients. Three functional groups were distinguished for CTNS mutations: cystinosin variant with residual cystin efflux activity (RA, residual activity), inactive cystinosin variant (IP, inactive protein), and absent protein (AP). PBMCs from patients with residual cystinosin activity generate significantly less osteoclasts than those obtained from patients of the other groups. In all groups, cysteamine exerts an inhibitory effect on osteoclastic differentiation at high doses. This study highlights a link between genotype and osteoclastic differentiation, as well as a significant impact of cysteamine therapy on this process in humans.
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    • Grant Information:
      2018 Cystinosis Research Foundation
    • Contributed Indexing:
      Keywords: bone; cysteamine; cystinosis; genotype; osteoclast
    • Accession Number:
      0 (Amino Acid Transport Systems, Neutral)
      0 (CTNS protein, human)
      5UX2SD1KE2 (Cysteamine)
    • Publication Date:
      Date Created: 20210928 Date Completed: 20211119 Latest Revision: 20211119
    • Publication Date:
      20221213
    • Accession Number:
      PMC8467406
    • Accession Number:
      10.3390/cells10092498
    • Accession Number:
      34572146