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

Thomas Quinaux (1, 2, 3, 4) , Aurélia Bertholet-Thomas (1, 2, 3, 4) , Aude Servais (5) , Olivia Boyer (6) , Isabelle Vrillon (7) , Julien Hogan (8) , Sandrine Lemoine (9, 10) , Ségolène Gaillard (11) , Candide Alioli (1) , Sophie Vasseur (12) , Cécile Acquaviva (12) , Olivier Peyruchaud (1) , Irma Machuca-Gayet (1) , Justine Bacchetta (1, 2, 3, 4)

1 LYOS - Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases
2 Centre de Référence des Maladies Rénales Rares
3 HFME - HCL - Centre de Référence des Maladies Rares du Calcium et du Phosphore
4 HFME - Hôpital Femme Mère Enfant [CHU - HCL]
5 Hôpital Necker - Enfants Malades [AP-HP]
6 MARHEA - Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker]
7 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
8 Hôpital Robert Debré
9 Hôpital Edouard Herriot [CHU - HCL]
10 Université de Lyon
11 CIC1407 - Centre d'Investigation Clinique [Bron]
12 HCL - Hospices Civils de Lyon

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 m2. 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.

Mots clés: bone; cysteamine; cystinosis; genotype; osteoclast

Domaines: Urologie et Néphrologie; Pharmacologie

Thomas Quinaux, Aurélia Bertholet-Thomas, Aude Servais, Olivia Boyer, Isabelle Vrillon, et al.. Response to Cysteamine in Osteoclasts Obtained from Patients with Nephropathic Cystinosis: A Genotype/Phenotype Correlation. Cells, 2021, 10 (9), pp.2498. ⟨10.3390/cells10092498⟩. ⟨hal-03390611⟩