Bone disease in nephropathic cystinosis is related to cystinosin-induced osteoclastic dysfunction

Claramunt-Taberner, Débora; Flammier, Sacha; Gaillard, Ségolène; Cochat, Pierre; Peyruchaud, Olivier; Machuca-Gayet, Irma; Bacchetta, Justine

doi:10.1093/ndt/gfx362

Cited by 13 publications

(32 citation statements)

References 11 publications

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“…Another proposed mechanism of skeletal damage is cysteamine toxicity. This hypothesis is based on recent in vitro evidence which shows that high doses of cysteamine may inhibit osteoblastic proliferation, and on the fact that cysteamine binds copper, a cofactor for lysyl oxidase, an enzyme that generates the aldehydes required for collagen crosslinking . We observed that cystine levels were not associated with BMD Z ‐scores, although all subjects in our NIH cohort were receiving cysteamine treatment at time of evaluation, eliminating our ability to compare the frequency of skeletal complications between treated and untreated groups.…”

Section: Discussionmentioning

confidence: 97%

“…There are several other mechanisms that could contribute to the high frequency of decreased bone mass and incidental fractures in nephropathic cystinosis. CTNS is expressed in osteoblasts and osteoclasts, and it has been suggested that mutations in this gene can impair the ability of bone marrow stromal cells to differentiate into osteoblasts. Cysteamine treatment may restore this ability, and additionally have beneficial antiresorptive effects by partly correcting the CTNS‐induced osteoclastic dysfunction .…”

Section: Discussionmentioning

confidence: 99%

“…Well‐characterized risk factors for skeletal morbidity include phosphate and calcium wasting, male primary hypogonadism, and chronic renal disease (CKD) associated with nephropathic cystinosis . Additionally, recent in vitro evidence suggests that CTNS mutations may lead to impaired osteoblast and osteoclast activity . Skeletal consequences are inadequately defined, with the current literature limited to a few small case series .…”

Section: Introductionmentioning

confidence: 99%

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Skeletal Consequences of Nephropathic Cystinosis

Florenzano

Ferreira

Nesterova

et al. 2018

Journal of Bone and Mineral Research

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Nephropathic cystinosis is a rare lysosomal storage disorder. Patients present in the first year of life with renal Fanconi syndrome that evolves to progressive chronic kidney disease (CKD). Despite the multiple risk factors for bone disease, the frequency and severity of skeletal disorders in nephropathic cystinosis have not been described. We performed systematic bone and mineral evaluations of subjects with cystinosis seen at the NIH (n = 30), including history and physical examination, serum and urine biochemistries, DXA, vertebral fracture assessment, skeletal radiographs, and renal ultrasound. Additionally, histomorphometric analyses are reported on six subjects seen at the UCLA Bone and Mineral Metabolism Clinic. In NIH subjects, mean age was 20 years (range, 5 to 44 years), 60% were CKD stages G1 to G4, and 40% had a renal transplant. Mean bone mineral density (BMD) Z-scores were decreased in the femoral neck, total hip, and 1/3 radius (p < 0.05). Low bone mass at one or more sites was present in 46% of subjects. Twenty-seven percent of subjects reported one or more long bone fractures. Thirty-two percent of subjects had incidental vertebral fractures, which were unrelated to transplant status. Long-bone deformity/bowing was present in 64%; 50% had scoliosis. Diffuse osteosclerosis was present in 21% of evaluated subjects. Risk factors included CKD, phosphate wasting, hypercalciuria, secondary hyperparathyroidism, hypovitaminosis D, male hypogonadism, metabolic acidosis, and glucocorticoid/immunosuppressive therapy. Sixty-one percent of the non-transplanted subjects had ultrasonographic evidence of nephrocalcinosis or nephrolithiasis. Histomorphometric analyses showed impaired mineralization in four of six studied subjects. We conclude that skeletal deformities, decreased bone mass, and vertebral fractures are common and relevant complications of nephropathic cystinosis, even before renal transplantation. Efforts to minimize risk factors for skeletal disease include optimizing mineral metabolism and hormonal status, combined with monitoring for nephrocalcinosis/nephrolithiasis. © 2018 This article is a U.S. Government work and is in the public domain in the USA.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Skeletal Consequences of Nephropathic Cystinosis

Florenzano

Ferreira

Nesterova

et al. 2018

Journal of Bone and Mineral Research

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“…Moreover, low doses of cysteamine in vitro stimulate osteoblastic differentiation and mineralization, with an inhibitory effect at higher doses, possibly explaining the bone toxicity observed in patients receiving high doses of cysteamine. Cystinosin may also be required for proper osteoclastic and osteoblastic activity …”

Section: Cystinosis Metabolic Bone Diseasementioning

confidence: 99%

“…Cystinosin may also be required for proper osteoclastic and osteoblastic activity. 35,36 3.3 | Assessing CMBD Serum mineral and enzyme values provide measures of bone health in both children and adults with cystinosis ( Table 2). In children with hypophosphatemic rickets, serum phosphate, bicarbonate, and potassium reflect renal losses and the efficacy of replacement therapy, and alkaline phosphatase (ALP) is a biomarker of rickets and osteomalacia.…”

Section: Pathogenesis Of Cmbdmentioning

confidence: 99%

Management of bone disease in cystinosis: Statement from an international conference

Hohenfellner

Rauch

Ariceta

et al. 2019

J of Inher Metab Disea

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Cystinosis is an autosomal recessive storage disease due to impaired transport of cystine out of lysosomes. Since the accumulation of intracellular cystine affects all organs and tissues, the management of cystinosis requires a specialized multidisciplinary team consisting of pediatricians, nephrologists, nutritionists, ophthalmologists, endocrinologists, neurologists' geneticists, and orthopedic surgeons. Treatment with cysteamine can delay or prevent most clinical manifestations of cystinosis, except the renal Fanconi syndrome. Virtually all individuals with classical, nephropathic cystinosis suffer from cystinosis metabolic bone disease (CMBD), related to the renal Fanconi syndrome in infancy and progressive chronic kidney disease (CKD) later in life. Manifestations of CMBD include hypophosphatemic rickets in infancy, and renal osteodystrophy associated with CKD resulting in bone deformities, osteomalacia, osteoporosis, fractures, and short stature. Assessment of CMBD involves monitoring growth, leg deformities, blood levels of phosphate, electrolytes, bicarbonate, calcium, and alkaline phosphatase, periodically obtaining bone radiographs, determining levels of critical hormones and vitamins, such as thyroid hormone, parathyroid hormone, 25(OH) vitamin D, and testosterone in males, and surveillance for nonrenal complications of cystinosis such as myopathy. Treatment includes replacement of urinary losses, cystine depletion with oral cysteamine, vitamin D, hormone replacement, physical therapy, and corrective orthopedic surgery. The recommendations in this article came from an expert meeting on CMBD that took place in Salzburg, Austria, in December 2016.

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Inhibition of Osteoclast Differentiation by 1.25-D and the Calcimimetic KP2326 Reveals 1.25-D Resistance in Advanced CKD

Bernardor

Flammier

Ranchin

et al. 2020

Journal of Bone and Mineral Research

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Active vitamin D analogs and calcimimetics are the main therapies used for treating secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). Peripheral blood mononuclear cells of 19 pediatric patients with CKD1-5D and 6 healthy donors (HD) were differentiated into mature osteoclasts with receptor activator of NF-κB ligand (RANKL) and macrophage colonystimulating factor (M-CSF). The effects of single or combined treatment with active vitamin D (1.25-D) and/or calcimimetic KP2326 were evaluated on osteoclastic differentiation and osteoclastic-mediated bone resorption. Although 1.25-D inhibited osteoclastic differentiation, a significant resistance to 1.25-D was observed when glomerular filtration rate decreased. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through a putative activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25-D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited osteoclast-mediated bone resorption. Both 1.25-D and KP2326 inhibit osteoclastic differentiation, however, to a different extent. There is a progressive resistance to 1.25-D in advanced CKD that is not found with KP2326. KP2326 also inhibits bone resorption. Given that 1.25-D has no effect on osteoclastic resorption activity and that calcimimetics also have direct anabolic effects on osteoblasts, there is an experimental rationale that could favor the use of decreased doses of 1.25-D with low doses of calcimimetics in SHPT in dialysis to improve the underlying osteodystrophy. However, this last point deserves confirmatory clinical studies.

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Bone disease in nephropathic cystinosis is related to cystinosin-induced osteoclastic dysfunction

Cited by 13 publications

References 11 publications

Skeletal Consequences of Nephropathic Cystinosis

Skeletal Consequences of Nephropathic Cystinosis

Management of bone disease in cystinosis: Statement from an international conference

Inhibition of Osteoclast Differentiation by 1.25-D and the Calcimimetic KP2326 Reveals 1.25-D Resistance in Advanced CKD

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