OverviewResearch

Bambino Gesù Children’s Hospital, Rome, Italy

  • Battafarano, G., et al. Emma, F. Taranta, A. Del Fattore, A. Bones/Disease Models

Intrinsic Bone Defects in Cystinotic Mice. Am J Pathol, 2019

  • Bone complication have been reported in cystinosis patients, where bone strength and thickness are decreased. In this study it was determined that bone defects in cystinotic mice are a result of dysfunction in bone remodelling and not renal loss of bone minerals due to Fanconi syndrome. The cystinotic mice show decreased bone density and volume. Blood markers that quantify bone remodelling activity were low. When the bones of the cystinotic mice were studies closely, impaired osteoblasts and osteoclasts function was revealed, which results in reduced bone remodelling activity.

Grants/Funding: Cystinosis Research Foundation and Italian Ministry of Healthy Ricerca Corrente

 

  • Conforti, A., et al. Emma, F. Bone/therapies

Cysteamine treatment restores the in vitro ability to differentiate along the osteoblastic lineage of mesenchymal stromal cells isolated from bone marrow of a cystinotic patient. J Transl Med, 2015

  • Cystinotic pluripotent bone cells isolated from a cystinosis patients bone marrow had a reduced ability to differentiate into osteoblasts (bone laying cells). Alkaline phosphatase is an enzyme that indicated bone osteoblast activity and bone growth. The Cystinotic cells had low alkaline phosphatase levels compared to healthy bone cells. Their capacity to differentiate into osteoblasts and alkaline phosphatase levels are restores when treated with cysteamine. ZONAB factor may be responsible for the lack of differentiation of cystinotic pluripotent cells into osteoblasts as it is seen to cause de-differentiation of cystinotic proximal tubular epithelial cells.

Grants/Funding: Bando Giovani Ricercatori, AIRC, HO2020 project “RETHRIM” and Regione Lazio

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children’s Hospital, Hannover, Germany

  • Ewert, A., et al. Haffner, D. Bones

Bone and Mineral Metabolism in Children with Nephropathic Cystinosis Compared with other CKD Entities. J Clin Endocrinol Metab, 2020

  • 49 pre-transplant Patients with nephropathic cystinosis were enrolled in a study. In this study bone and mineral parameters were measured and compared to 80 other Chronic Kidney Disease patients. The cystinosis patients showed an 11-fold increase in the likely hood of short stature, bone deformities and skeletal issues requiring surgery compared with the other CKD patients. This suggests that the bone issues are not be caused by mineral loss in the kidney, but instead by impaired bone remodelling and increased bone reabsorption. Low PTH, calcium and phosphate levels were common which are required for healthy bones. Kidney transplant did not fully resolve the issues observed.

Grants/Funding:

 

 

Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France

  • Claramunt-Taberner, D., et al. Bacchetta, J. Bones

Bone disease in nephropathic cystinosis is related to cystinosin-induced osteoclastic dysfunction. Nephrol Dial Transplant, 2018

  • Of the 10 nephropathic cystinosis patients enrolled in this study 7 had past or present bone issues including fractures and bone pain. All the patients were in their teens to early thirties. Abnormalities in the bone cortex (outer surface) including low bone density and significantly lower bone thickness and bone cortical thickness were seen in the post and pre transplant patients.

Grants/Funding: Raptor/Horizon Pharmaceuticals

  • Bertholet-Thomas, A., et al. Bacchetta, J.                                           Bones/Cysteamine

Teenagers and young adults with nephropathic cystinosis display significant bone disease and cortical impairment. Pediatr Nephrol, 2018

  • Osteoclasts and from nephropathic cystinosis patients bone marrow was studied to determine their function without cystinosin. Osteoclastic resorptive activity is increased in CTNS deficient osteoclasts, but low doses of cysteamine lower this activity to normal levels. Low doses of cysteamine also stimulate osteoblastic differentiation and mineralization which is reversed at high doses. Bone toxicity is observed at high doses of cysteamine might be explained by this inhibition of osteoblasts. Thus, low doses of cysteamine have a dual effect on bones, reducing reabsorption and increasing mineralization. Further understanding of these mechanisms may improve clinical management of nephropathic cystinosis. `

Grants/Funding: Foundation du Rein, INSERM Université Claude Bernard Lyon and ANR grant LYSBONE.