Chronic Kidney Disease–Induced Vascular Calcification Impairs Bone Metabolism

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).

New Insights to the Crosstalk between Vascular and Bone Tissue in Chronic Kidney Disease–Mineral and Bone Disorder

“…The gene analysis also showed a specific upregulation of the gene Sost, coding for the canonical Wnt inhibitor sclerostin, and downregulation of Wnt target genes. These novel results indicated not only that vascular calcification inhibited the anabolic Wnt pathway in bone, but it also affected several pathways representing a complex effect on bone metabolism, suggesting several factors secreted by the uremic calcified aorta (Figure 2) [80]. CKD rat was transplanted into a normal isogenic recipient.…”

“…Recent research has identified several factors in the uremic condition to be involved in vascular disease and development of vascular calcification such as uremic toxins, reactive oxygen species, DNA damage, cell senescence, inflammation, loss of local and system calcification inhibitors, secondary calciprotein particles (CPPs), and kidney-derived injury factors [73][74][75][76]. Our group has studied the uremic vasculopathy in different experimental models of kidney disease [66,[77][78][79][80][81]. Recently, we have reviewed the role of the disturbed circadian clock in uremic vasculopathy and showed that it is a new important factor in the pathogenesis [81,82].…”

“…Since several signal molecules induced in the vasculature in the process of calcification are also found at higher levels in plasma in CKD, we speculated whether these factors were secreted by the vessel and had endocrine effect on bone, thereby linking the dysfunction of the two tissues. In order to examine our hypothesis of a vascular-bone tissue crosstalk, we developed a novel model of aorta transplantation where the calcified aorta from 5/6 nephrectomized rats (treated with a high phosphate diet and calcitriol) was transplanted into a normal recipient rat (Figure 2) [80]. In this new model, other factors in the uremic condition are excluded, and only the presence of a calcified graft remains in a healthy rat.…”

The Vascular Circadian Clock in Chronic Kidney Disease

“…Structural and functional changes in the vasculature are observed early in CKD, including the altered expression of genes related to the developmental program and the contractility of VSMC, vascular stiffness and endothelial dysfunction [ 47 , 82 ]. Dedifferentiated VSMC are susceptible to osteoblastic transformation and in more advanced stages of CKD to the progressive accumulation of calcium crystals in the extracellular matrix and progressive calcification of neointima and lamina media of the vascular wall [ 82 , 83 ].…”

Predictive Value of Measures of Vascular Calcification Burden and Progression for Risk of Death in Incident to Dialysis Patients

“…Vascular calcification (VC) is a useful marker of cardiovascular disease and several methods are available for the assessment of their presence and extension [1][2][3][4][5]. Although the pathogenesis of VC is not well established, several studies suggest that the prevalence of VC increases as renal function declines, likely due to the many metabolic abnormalities that characterize chronic kidney disease (CKD) [3,5,6]. Irrespective of the noxious mechanism responsible for VC deposition and progression, the data suggest that the risk of unfavorable outcome is higher for greater VC burden [2,5].…”