Osteoclasts obtained from patients with nephropathic cystinosis with residual cystinosin activity display a peculiar sensitivity to cysteamine

Presented by Professor Justine Bacchetta, Centre de Référence des Maladies Rénales Rares, Centre de Référence des Maladies Rares du Calcium et du Phosphore, Hôpital Femme Mère Enfant, Bron, and INSERM 1033 Research Unit, Lyon, France

Authors: T Quinaux1-2, A Bertholet-Thomas1-2, G Deschenes3, O Boyer4, M Pongas5, S Lemoine6, A Servais7, S Gaillard8, D Platel2, C Acquaviva-Bourdain9, I Machuca-Gayet2-*, J Bacchetta1,2,*

Lay Summary

Despite cysteamine therapy, patients with cystinosis may display severe bone symptoms, and the concept of “cystinosis metabolic bone disease” (CMD) is currently emerging. Its exact underlying pathophysiology remains unclear, but at least five complementary entities can explain CMBD: 1/ long-term consequences of hypophosphatemic rickets and renal Fanconi syndrome together with iatrogenic effects of its supportive management, 2/ deficiency in nutrition and micro-nutrition, 3/ hormonal disturbances such as hypothyroidism, hypogonadism, hypoparathyroidism and resistance to growth hormone, 4/ myopathy, and 5/ intrinsic and iatrogenic bone defects such as direct consequences of CTNS mutation and cysteamine on osteoblasts and osteoclasts.

Purpose/Objectives of Study and a Brief Background Statement

The main objectives of the CYSTEABONE study (NCT03919981) were to determine in vitro the impact of CTNS mutations and cysteamine therapy on human osteoclasts and to carry out a genotype-phenotype analysis in terms of osteoclastic differentiation and response to cysteamine therapy.


Human osteoclasts were differentiated from peripheral blood mononuclear cells (PBMCs) of  patients. Cells were treated with increasing doses of cysteamine – 0 µM, 50 µM, 200 µM – and then assessed for osteoclastic differentiation and RNA expression profile. Results are presented as median(IQR).


A total of 17 patients were included, mainly pediatric patients, at a median age of 14(7-18) years, and a median eGFR of 64(50-105) ml/min per 1.73m². Most patients (71%) were under conservative kidney management (CKM). The others were kidney transplant recipients.

High dose cysteamine (200 µM) decreased the propensity of patients-derived mononuclear progenitors to generate osteoclasts. Interestingly, monocyte progenitors from patients with residual cystinosin activity showed a peculiar sensitivity to cysteamine, which displayed a biphasic effect on these progenitors depending on its concentration (50 vs. 200 µM). Cysteamine also had a significant impact on the RNA expression profile of patients’ osteoclasts, which varied according to its concentration.


The effect of cysteamine on bone metabolism depends on several factors, including the concentration at which it is administered and the genotype of treated patients. High dose cysteamine decreases the propensity of patients-derived mononuclear progenitors to generate osteoclasts, whatever their genotype. However, the study of genotype/phenotype correlations highlights a link between genotype and osteoclastic response to various concentrations of cysteamine in humans. These findings constitute a first step towards the implementation of personalized medicine in cystinosis, according to the genetic background of each patient.

Selected references

– Hohenfellner K, et al. Management of bone disease in cystinosis: Statement from an international conference. J Inherit Metab Dis. 2019

– Machuca-Gayet I, et al. Bone Disease in Nephropathic Cystinosis: Beyond Renal Osteodystrophy. Int J Mol Sci. 2020 Epub. doi: 10.3390/ijms21093109.

Author Affiliations

  1. Centre de Référence des Maladies Rénales Rares, Centre de Référence des Maladies Rares du Calcium et du Phosphore, Hôpital Femme Mère Enfant, Bron, France
  2. INSERM 1033 Research Unit, Lyon, France
  3. Service de Néphrologie, APHP-Hôpital Robert Debré, Paris, France
  4. Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
  5. Service de Néphrologie Pédiatrique, Hôpital d’Enfants, CHRU de Nancy, France
  6. Service de Néphrologie, Hôpital Edouard Herriot, Lyon, France
  7. Service de Néphrologie, Hôpital Necker, Paris, France
  8. EPICIME-CIC 1407, Bron, France
  9. Service de Biochimie et Biologie Moléculaire, Hospices Civils de Lyon, Bron, France

*-   Equally contributing authors

Disclosure of interests

None to declare

Financial support

JB and IMG received a research grant from the Cystinosis Research Foundation for the CYSTEA-BONE project. TQ received a personal grant from the Agence Régionale de Santé Grand Est (Année Recherche Fellowship).