Chronic Kidney Disease–Induced Vascular Calcification Impairs Bone Metabolism

• Published in: Journal of bone and mineral research Vol. 36; no. 3; pp. 510 - 522
• Main Authors: Mace, Maria L, Gravesen, Eva, Nordholm, Anders, Egstrand, Soeren, Morevati, Marya, Nielsen, Carsten, Kjaer, Andreas, Behets, Geert, D'Haese, Patrick, Olgaard, Klaus, Lewin, Ewa
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.03.2021; Wiley Subscription Services, Inc
• Subjects: ANIMAL MODEL; Animal models; ANKH protein; Ankylosis; Aorta; Arteries; Arteriosclerosis; Bone growth; BONE HISTOMORPHOMETRY; Bone loss; Bone matrix; Bone mineral density; Bone turnover; BONE μCT; Calcification; Calcification (ectopic); Coronary vessels; Extracellular matrix; Kidney diseases; Metabolism; Mineralization; mRNA; Original; Osteoblasts; Osteoclasts; Osteogenesis; Osteoid; Osteopontin; SOST protein; SYSTEMS BIOLOGY–BONE INTERACTORS; Transplantation; Wnt protein; WNT/β‐CATENIN/LRPs; BONE HISTOMORPHOMETRY; BONE μCT; ANIMAL MODEL; WNT/β-CATENIN/LRPs; SYSTEMS BIOLOGY-BONE INTERACTORS
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.4203

ABSTRACT An association between lower bone mineral density (BMD) and presence of vascular calcification (VC) has been reported in several studies. Chronic kidney disease (CKD) causes detrimental disturbances in the mineral balance, bone turnover, and development of severe VC. Our group has previously demonstrated expression of Wnt inhibitors in calcified arteries of CKD rats. Therefore, we hypothesized that the CKD‐induced VC via this pathway signals to bone and induces bone loss. To address this novel hypothesis, we developed a new animal model using isogenic aorta transplantation (ATx). Severely calcified aortas from uremic rats were transplanted into healthy rats (uremic ATx). Transplantation of normal aortas into healthy rats (normal ATx) and age‐matched rats (control) served as control groups. Trabecular tissue mineral density, as measured by μCT, was significantly lower in uremic ATx rats compared with both control groups. Uremic ATx rats showed a significant upregulation of the mineralization inhibitors osteopontin and progressive ankylosis protein homolog in bone. In addition, we found significant changes in bone mRNA levels of several genes related to extracellular matrix, bone turnover, and Wnt signaling in uremic ATx rats, with no difference between normal ATx and control. The bone histomorphometry analysis showed significant lower osteoid area in uremic ATx compared with normal ATx along with a trend toward fewer osteoblasts as well as more osteoclasts in the erosion lacunae. Uremic ATx and normal ATx had similar trabecular number and thickness. The bone formation rate did not differ between the three groups. Plasma biochemistry, including sclerostin, kidney, and mineral parameters, were similar between all three groups. ex vivo cultures of aorta from uremic rats showed high secretion of the Wnt inhibitor sclerostin. In conclusion, the presence of VC lowers BMD, impairs bone metabolism, and affects several pathways in bone. The present results prove the existence of a vasculature to bone tissue cross‐talk. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).