Calcimimetics maintain bone turnover in uremic rats despite the concomitant decrease in parathyroid hormone concentration
| Autor: | Victor Lorenzo, Julio M. Martinez-Moreno, Juan R. Muñoz-Castañeda, Cristian Rodelo-Haad, Rafael Santamaria, Noemi Vergara, M. Victoria Pendón-Ruiz de Mier, Carmen Herencia, Ignacio González López, William G. Richards, Catarina Carvalho, Carmen Pineda, Escolastico Aguilera-Tejero, Antonio Casado-Díaz, João M. Frazão, Arnold J. Felsenfeld, María E. Rodríguez-Ortiz, Juan M. Díaz-Tocados, Yolanda Almaden, Mariano Rodriguez |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Calcimimetic 030232 urology & nephrology Parathyroid hormone Calcimimetic Agents bone Bone remodeling 03 medical and health sciences 0302 clinical medicine Internal medicine Bone cell Phenethylamines medicine CaSR Animals Humans Rats Wistar Osteoblasts Chemistry Osteoid Biphenyl Compounds Osteoblast medicine.disease mineral metabolism Rats calcimimetic Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure Nephrology Parathyroid Hormone Calcilytic Kidney Failure Chronic Secondary hyperparathyroidism Hyperparathyroidism Secondary Bone Remodeling Receptors Calcium-Sensing hormones hormone substitutes and hormone antagonists chronic kidney disease |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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