High calcium, phosphate and calcitriol supplementation leads to an osteocyte-like phenotype in calcified vessels and bone mineralisation defect in uremic rats
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A link between vascular calcification and bone anomalies has been suggested in chronic kidney disease (CKD) patients with low bone turnover disease. We investigated the vascular expression of osteocyte markers in relation to bone microarchitecture and mineralization defects in a model of low bone turnover CKD rats with vascular calcification. CKD with vascular calcification was induced by 5/6 nephrectomy followed by high calcium and phosphate diet, and vitamin D supplementation (Ca/P/VitD). CKD + Ca/P/VitD group (n = 12) was compared to CKD + normal diet (n = 12), control + normal diet (n = 8) and control + Ca/P/VitD supplementation (n = 8). At week 6, tibia, femurs and the thoracic aorta were analysed by Micro-Ct, histomorphometry and for expression of osteocyte markers. High Ca/P/VitD treatment induced vascular calcification only in CKD rats, suppressed serum parathyroid hormone levels and led to higher sclerostin, DKK1 and FGF23 serum levels. Expression of sclerostin, DKK1 and DMP1 but not FGF23 were increased in calcified vessels from CKD + Ca/P/VitD rats. Despite low parathyroid hormone levels, tibia bone cortical thickness was significantly lower in CKD + Ca/P/VitD rats as compared to control rats fed a normal diet, which is likely the result of radial growth impairment. Finally, Ca/P/VitD treatment in CKD rats induced a bone mineralization defect, which is likely explained by the high calcitriol dose. In conclusion, Ca/P/VitD supplementation in CKD rats induces expression of osteocyte markers in vessels and bone mineralisation anomalies. Further studies should evaluate the mechanisms of high dose calcitriol-induced bone mineralisation defects in CKD.
KeywordsRenal osteodystrophy Vascular calcification Bone Osteocyte Mineralisation defects
Dr. Mac-Way holds a scholarship from FRQ-S (Grant no. 32661) and KRESCENT program from the CIHR-Kidney Foundation of Canada. This study was supported by a grant from the Kidney Foundation of Canada (Grant no. KFOC160013) and from the Department of Medicine and la Fondation du CHU de Québec from Université Laval. Dr. Agharazii holds a research chair in nephrology from Université Laval.
MA, RL and FMW conceived and designed the study. SKB and FMW performed the statistical analyses. SKB, DV and RVU conducted animal experimentations, tissue specimens handling, and interpreted the findings. SP and FMW were in charge of the bone histomorphometry analysis. SKB and FMW wrote the first draft and revised all subsequent versions. All authors provided their input, expertise and critical review of the paper. All authors read and approved the final version of the paper. FMW had full access to the data and takes responsibility for the integrity and accuracy of the data analysis.
Compliance with ethical standards
Conflict of interest
All authors have no conflicts of interest.
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