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

Abstract

Vasculature plays a key role in bone development and the maintenance of bone tissue throughout life. The two organ systems are not only linked in normal physiology, but also in pathophysiological conditions. The chronic kidney disease-mineral and bone disorder (CKD-MBD) is still the most serious complication to CKD, resulting in increased morbidity and mortality. Current treatment therapies aimed at the phosphate retention and parathyroid hormone disturbances fail to reduce the high cardiovascular mortality in CKD patients, underlining the importance of other factors in the complex syndrome. This review will focus on vascular disease and its interplay with bone disorders in CKD. It will present the very late data showing a direct effect of vascular calcification on bone metabolism, indicating a vascular-bone tissue crosstalk in CKD. The calcified vasculature not only suffers from the systemic effects of CKD but seems to be an active player in the CKD-MBD syndrome impairing bone metabolism and might be a novel target for treatment and prevention.

Keywords: TGF-β signaling; Wnt pathway; activin A; dickkopf-1; renal osteodystrophy; sclerostin; tissue crosstalk; uremic vasculopathy; vascular calcification.

Figure 1

Hypothesis of pathological endothelial–vascular bone-like cell crosstalk in vascular calcification in CKD. A kind of osteomimicry? In addition to the endothelial to mesenchymal transition (EndMT) shift of the endothelial cells in CKD, the phenotypic shift of the endothelium may include expression of signals to promote vascular calcification and so mimic the endothelial cell of the bone vasculature. The de-differentiated VSMC/vascular bone-like cell may also communicate with the nearby endothelial cells, promoting vascular bone formation.

Figure 2

Pathological vascular calcification–bone tissue crosstalk in CKD The calcified aorta from CKD rat was transplanted into a normal isogenic recipient. The presence of the calcified aorta graft had a dramatic effect on bone of the recipient. In comparison to normal rats transplanted with a normal aorta graft, normal rats transplanted with the calcified aorta graft have lower trabecular tissue mineral density and osteoid area. These recipients of the calcified aorta graft had significant changes in expression of several markers related to bone formation, resorption, and RANKL. Sost coding for sclerostin was significantly upregulated with a downregulation of several Wnt target genes. The mineralization inhibitors osteopontin and progressive ankylosis protein homolog (ANKH) were upregulated by 3–4 fold [80].

Figure 3

Secretion of Wnt inhibitors and TGF-β ligand from the calcified vasculature in CKD—a new pathway by which the calcified vasculature plays an active role in CKD-MBD Ex vivo incubation of the calcified aorta from CKD rats showed large secretion of sclerostin, Dkk1, and activin A [80].

Figure 4

Negative spiral of de-mineralization of bone and mineralization of the vasculature. Osteopontin may play a role in the ‘calcification paradox’ during the process of vascular calcification the mineralization inhibitor osteopontin (OPN) is upregulated to be one of the most expressed genes in the diseased vessel. We propose that the stimulators of OPN expression in the vasculature also stimulate OPN expression in bone as shown in our recent study [80]. Disturbances in bone mineralization may have a negative impact on the vasculature with further precipitation of calcium-phosphate crystals. The novel concept of the pathological vascular–bone tissue crosstalk may provide a new explanation to the ‘calcification paradox’.