Calcimimetics maintain bone turnover in uremic rats despite the concomitant decrease in parathyroid hormone concentration

• Type: Article in International Scientific Journal
• Date: 2019

Authors

Diaz Tocados, JM (Author) Other; Rodriguez Ortiz, ME (Author) Other; Almaden, Y (Author) Other; Pineda, C (Author) Other; Martinez Moreno, JM (Author) Other; Herencia, C (Author) Other; Vergara, N (Author) Other; de Mier, MVPR (Author) Other; Santamaria, R (Author) Other; Rodelo Haad, C (Author) Other; Casado Diaz, A (Author) Other; Lorenzo, V (Author) Other; Carvalho, C (Author) Other; João Frazão (Author) FMUP; Felsenfeld, AJ (Author) Other; Richards, WG (Author) Other; Aguilera Tejero, E (Author) Other; Rodriguez, M (Author) Other; Lopez, I (Author) Other; Munoz Castaneda, JR (Author) Other

Journal

Title: Kidney International

Vol. 95

Pages: 1064-1078

ISSN: 0085-2538

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 33 Citations

Scopus - 34 Citations

Other information

Authenticus ID: P-00Q-GAN

DOI: 10.1016/j.kint.2018.12.015

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Dissemination

No. of pages: 15