Pathophysiology of Vascular Calcification and Bone Loss: Linked Disorders of Ageing?

Abstract

Vascular Calcification (VC), low bone mass and fragility fractures are frequently observed in ageing subjects. Although this clinical observation could be the mere coincidence of frequent age-dependent disorders, clinical and experimental data suggest that VC and bone loss could share pathophysiological mechanisms. Indeed, VC is an active process of calcium and phosphate precipitation that involves the transition of the vascular smooth muscle cells (VSMCs) into osteoblast-like cells. Among the molecules involved in this process, parathyroid hormone (PTH) plays a key role acting through several mechanisms which includes the regulation of the RANK/RANKL/OPG system and the Wnt/ß-catenin pathway, the main pathways for bone resorption and bone formation, respectively. Furthermore, some microRNAs have been implicated as common regulators of bone metabolism, VC, left ventricle hypertrophy and myocardial fibrosis. Elucidating the common mechanisms between ageing; VC and bone loss could help to better understand the potential effects of osteoporosis drugs on the CV system.

Keywords: bone fractures; bone loss; fracture risk; mineral bone disorders; osteoporosis; vascular calcification.

Figure 1

X-ray image of a 71 years old woman with aortic calcifications, low bone density and a vertebral fracture.

Figure 2

Promoters and inhibitors of vascular calcification. RANKL, receptor activator of nuclear factor-kappa B Ligand; LDL, low-density lipoprotein; ALP, alkaline phosphatase; Ca, calcium; BMP, bone morphogenetic proteins; P, phosphate; TNF-α, tumor necrosis factor-alpha; Vit D3, calcitriol; MGP, matrix GLA protein, HDL, High-density lipoprotein; OPG, osteoprotegerin; OPN, osteopontin; FGF23, fibroblast growth factor 23. (Modified with permission of Oxford University Press from [12]).

Figure 3

Main pathways of bone metabolism (RANK-RANKL-OPG-LGR4 System and Wnt/β-catenin) and their involvement in vascular calcification, and main effects of parathyroid hormone (PTH) and phosphorus (P) on both pathways. In bone, the osteoblast synthesizes and secretes RANKL and OPG. The binding of RANKL to RANK in osteoclast precursors induces their activation, maturation and survival, and therefore osteoclastogenesis and bone resorption. The osteoblast also synthesizes OPG that prevents the RANKL-RANK union, inhibiting osteoclastogenesis. In addition RANKL can bind LGR4 triggering bone formation signals and bone mineralization. In vascular smooth muscle cells (VSMC), the binding of RANKL to both RANK and LGR4 induces mineralization signals and vascular calcification. The union of RANKL to OPG, prevents calcification of VSMC. The Wnt/β-catenin’s pathway activation promotes the transcription of bone forming genes, regulating pre-osteoblast differentiation and osteoblast activity. The Wnt/β-catenin pathway has several inhibitors such us Dickkopf1 (Dkk1), sclerostin (Sost), and the secreted Frizzle related proteins (sFRPs), which are able to block the Wnt/β-catenin pathway, inhibiting the osteoblast differentiation and survival. The Wnt/ß-catenin pathway is also involved in the process of vascular calcification, though there is still controversy regarding the regulation of inhibitors of the Wnt/ß-catenin pathway in the process of vascular calcification. MicroRNAs (miRNAs) can regulate bone formation and/or resorption and mineralization but also can promote or inhibit VSMC calcification. Pointed arrow means activation and stop arrow means inhibition or blockage. In case of controversy in the literature, the most accepted option is included in the figure accompanied by a “?” symbol.