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Review
. 2020 Apr 28;21(9):3109.
doi: 10.3390/ijms21093109.

Bone Disease in Nephropathic Cystinosis: Beyond Renal Osteodystrophy

Irma Machuca-Gayet  1 , Thomas Quinaux  1   2 , Aurélia Bertholet-Thomas  2 , Ségolène Gaillard  3 , Débora Claramunt-Taberner  1 , Cécile Acquaviva-Bourdain  4 , Justine Bacchetta  1   2   5
Affiliations
Review

Bone Disease in Nephropathic Cystinosis: Beyond Renal Osteodystrophy

Irma Machuca-Gayet et al. Int J Mol Sci. .

Abstract

Patients with chronic kidney disease (CKD) display significant mineral and bone disorders (CKD-MBD) that induce significant cardiovascular, growth and bone comorbidities. Nephropathic cystinosis is an inherited metabolic disorder caused by the lysosomal accumulation of cystine due to mutations in the CTNS gene encoding cystinosin, and leads to end-stage renal disease within the second decade. The cornerstone of management relies on cysteamine therapy to decrease lysosomal cystine accumulation in target organs. However, despite cysteamine therapy, patients display severe bone symptoms, and the concept of "cystinosis metabolic bone disease" is currently emerging. Even though its exact pathophysiology remains unclear, at least five distinct but complementary entities can explain bone impairment in addition to CKD-MBD: long-term consequences of renal Fanconi syndrome, malnutrition and copper deficiency, hormonal disturbances, myopathy, and intrinsic/iatrogenic bone defects. Direct effects of both CTNS mutation and cysteamine on osteoblasts and osteoclasts are described. Thus, the main objective of this manuscript is not only to provide a clinical update on bone disease in cystinosis, but also to summarize the current experimental evidence demonstrating a functional impairment of bone cells in this disease and to discuss new working hypotheses that deserve future research in the field.

Keywords: Bone; CKD-MBD; Nephropathic cystinosis; Orphan disease; Osteoblast; Osteoclast; Renal osteodystrophy (ROD); mTor signaling.

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Conflict of interest statement

A.B.-T. has received speaker fees and travel grants from Chiesi.

Figures

Figure 1
Figure 1
Current understanding of osteoblastic and osteoclastic defects in cystinosis, resulting from a combination of cystinosin deficiency and cysteamine effects. Mesenchymal stem cells (MSCs) isolated from a patient with cystinosis display a reduced ability to differentiate into osteoblasts, which can be reverted after cysteamine treatment. In vitro mineralization assays demonstrate a reduced ability to release mineralized nodules from cystinotic osteoblasts as compared to control cells. In vitro low doses of cysteamine (50 µM) stimulate osteoblastic differentiation and mineralization, with an inhibitory effect at higher doses (200 µM). Cystinosis favors osteoclastogenesis, mononuclear progenitors being more prone to generate osteoclasts than controls. Cysteamine has no effect on osteoclastic differentiation whatever the origin of the donors and the doses tested. However, it is noteworthy that cysteamine displays a beneficial anti-resorptive effect: in controls, a 50%-inhibition of resorption activity is observed with 50µM. As for patients, the decreased osteoclastic activity is detectable and significant only at 200 µM. WT, Wild-type; Ctns-/-, gene knockout (murine model); CTNS-/-, cystinotic patients; MSC, Mesenchymal stem cell; PBMC, Peripheral blood mononuclear cell. Black arrow: no treatment; Blue arrow: cysteamine treatment. Pill icon: cysteamine - 50 µM (one pill), 200µM (two pills). Top right pictures: mineralization nodules magnification (Von Kossa staining); Bottom right illustrations: osteoclastic resorption pits.
Figure 2
Figure 2
Hypothetical regulation of mtorc1 activation in osteoclasts derived from healthy donors and from patients with nephropathic cystinosis. The Ragulator-Rag Complex has a key role in mTOR signaling regulation. The Ragulator, along with the Rag GTPases, are necessary for the localization of mTORC1 to the lysosome surface. When enough amino acids are present, Rag GTPases become activated, which leads to the translocation of mTORC1 from the cytoplasm to the lysosome surface. This process allows mTORC1 to bind to Rheb, which induces the kinase activity of mTORC1. Absence or severe mutation of cystinosin, a protein interacting with the Ragulator-Rag complex, might prevent the activation of mTORC1 by Rheb, which would increase the final number of osteoclasts at the end of the differentiation process. mTORC1, mammalian target of rapamycine complex 1.
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