RT Journal Article
T1 Calcimimetics maintain bone turnover in uremic rats despite the concomitant decrease in parathyroid hormone concentration.
A1 Diaz-Tocados, Juan M
A1 Rodriguez-Ortiz, Maria E
A1 Almaden, Yolanda
A1 Pineda, Carmen
A1 Martinez-Moreno, Julio M
A1 Herencia, Carmen
A1 Vergara, Noemi
A1 Pendon-Ruiz de Mier, M Victoria
A1 Santamaría, Rafael
A1 Rodelo-Haad, Cristian
A1 Casado-Diaz, Antonio
A1 Lorenzo, Victor
A1 Carvalho, Catarina
A1 Frazão, João M
A1 Felsenfeld, Arnold J
A1 Richards, William G
A1 Aguilera-Tejero, Escolástico
A1 Rodriguez, Mariano
A1 Lopez, Ignacio
A1 Muñoz-Castañeda, Juan R
K1 CaSR
K1 Bone
K1 Calcimimetic
K1 Chronic kidney disease
K1 Mineral metabolism
K1 Parathyroid hormone
AB Calcimimetics decrease parathyroid hormone (PTH) secretion in patients with secondary hyperparathyroidism. The decrease in PTH should cause a reduction in bone turnover; however, the direct effect of calcimimetics on bone cells, which express the calcium-sensing receptor (CaSR), has not been defined. In this study, we evaluated the direct bone effects of CaSR activation by a calcimimetic (AMG 641) in vitro and in vivo. To create a PTH "clamp," total parathyroidectomy was performed in rats with and without uremia induced by 5/6 nephrectomy, followed by a continuous subcutaneous infusion of PTH. Animals were then treated with either the calcimimetic or vehicle. Calcimimetic administration increased osteoblast number and osteoid volume in normal rats under a PTH clamp. In uremic rats, the elevated PTH concentration led to reduced bone volume and increased bone turnover, and calcimimetic administration decreased plasma PTH. In uremic rats exposed to PTH at 6-fold the usual replacement dose, calcimimetic administration increased osteoblast number, osteoid surface, and bone formation. A 9-fold higher dose of PTH caused an increase in bone turnover that was not altered by the administration of calcimimetic. In an osteosarcoma cell line, the calcimimetic induced Erk1/2 phosphorylation and the expression of osteoblast genes. The addition of a calcilytic resulted in the opposite effect. Moreover, the calcimimetic promoted the osteogenic differentiation and mineralization of human bone marrow mesenchymal stem cells in vitro. Thus, calcimimetic administration has a direct anabolic effect on bone that counteracts the decrease in PTH levels.
PB Elsevier
YR 2018
FD 2018-12-06
LK http://hdl.handle.net/10668/13716
UL http://hdl.handle.net/10668/13716
LA en
NO Díaz-Tocados JM, Rodríguez-Ortiz ME, Almadén Y, Pineda C, Martínez-Moreno JM, Herencia C, et al. Calcimimetics maintain bone turnover in uremic rats despite the concomitant decrease in parathyroid hormone concentration. Kidney Int. 2019 May;95(5):1064-1078
NO We thank Daniela Sousa from the INEB/I3S institute and the Nephrology Unit of the Hospital São João for kind assistance with bone histomorphometry. The calcimimetic AMG 641 was a kind gift from AMGEN. This work was partially supported by a Spanish Government Grant from National Program IþDþI 2008-2011 from the National Institute of Health Carlos III (PI14/00638 and PI14/00467 and PI 17/01010) with co-financing from European Funds (FEDER). JM, D-T, and NV are supported by the Ministry of Economy, Innovation,Science and Employment of the Andalusian Local Government (CVI7925). MERO is the recipient of a “Sara Borrell” research contract from the National Institute of Health Carlos III. YA and JRMC are senior researchers supported by the Nicolás Monardes Programme, Ministry of Health, Andalusian Health Service (Andalusian Local Government).
DS RISalud
RD Apr 10, 2025