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Díaz‐Tocados, Juan Miguel; Rodríguez‐Ortiz, María Encarnación; Herencia, Carmen; López‐Baltanás, Rodrigo; Jurado‐Montoya, Daniel; García‐Saez, Raquel María; Valdés‐Díaz, Karen; Martínez‐Moreno, Julio Manuel; Santamaría, Rafael; Pendón‐Ruiz de Mier, María Victoria; Rodelo‐Haad, Cristian; Frazão, João Miguel; Felsenfeld, Arnold J.; Rodríguez, Mariano; Almadén, Yolanda; Muñoz‐Castañeda, Juan Rafael
The FASEB journal, 15 June 2024, 2024-06-15, 20240615, Letnik: 38, Številka: 11Journal Article
Calcitriol and calcimimetics are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). Calcitriol administration and the subsequent increase in serum calcium concentration decrease parathyroid hormone (PTH) levels, which should reduce bone remodeling. We have previously reported that, when maintaining a given concentration of PTH, the addition of calcimimetics is associated with an increased bone cell activity. Whether calcitriol administration affects bone cell activity while PTH is maintained constant should be evaluated in an animal model of renal osteodystrophy. The aim of the present study was to compare in CKD PTH‐clamped rats the bone effects of calcitriol and calcimimetic administration. The results show that the administration of calcitriol and calcimimetic at doses that induced a similar reduction in PTH secretion produced dissimilar effects on osteoblast activity in 5/6 nephrectomized (Nx) rats with secondary hyperparathyroidism and in Nx rats with clamped PTH. Remarkably, in both rat models, the administration of calcitriol decreased osteoblastic activity, whereas calcimimetic increased bone cell activity. In vitro, calcitriol supplementation inhibited nuclear translocation of β‐catenin and reduced proliferation, osteogenesis, and mineralization in mesenchymal stem cells differentiated into osteoblasts. In conclusion, besides the action of calcitriol and calcimimetics at parathyroid level, these treatments have specific effects on bone cells that are independent of the PTH level. In vivo studies used 5/6 nephrectomy with parathyroidectomy and replacement of exogenous PTH to eliminate the osteogenic effect of PTH comparing the bone effects of calcitriol vs calcimimetic. The osteogenesis of mesenchymal stem cells in presence of calcitriol was also evaluated. Results show calcimimetic increases bone formation, while calcitriol reduces it. In vitro, calcitriol presence reduces mineralization and osteogenesis of stem cells into osteoblasts. In this experimental study and independently of PTH, we demonstrate that calcitriol administration reduces bone formation.
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