RANKL system in vascular and valve calcification with aging

Abstract

Vascular and cardiac valve calcification is associated with cardiovascular mortality in the general population. Increasing clinical and experimental evidence suggests that inflammation accelerates the progression of calcification, which has molecules in common with bone metabolism. For example, osteopontin (OPN), osteoprotegerin (OPG), receptor activator of the nuclear factor κB ligand (RANKL), and alkaline phosphatase (ALP) are proposed to play central roles in the calcification or demineralization of atherosclerotic lesions and the calcification of cardiac valves. Abnormalities in the balance of these proteins may lead to perturbations in vascular/valve calcification. "How to prevent calcification" is a common task based on conventional data; however, several pathological findings indicate that heavily calcified plaques are stable, which may not lead to coronary events. Vulnerable plaques tend to be either noncalcified or only mildly or moderately calcified. "How to treat calcification," which depends on the details of the specific patient, thus remains a difficult challenge. In addition to the detection of calcification, characterization as well as quantification of it is necessary for optimal treatment of this pathology in the future.

Keywords: Cardiac valve calcification; ECs; OPG; Osteoporosis; RANK; RANKL; VICs; VSMCs; Vascular calcification.

Fig. 1

Scheme of vascular calcification through the RANK/RANKL/OPG axis. In vascular cells, RANK is expressed in both ECs and smooth muscle cells (VSMCs), and RANKL is primarily expressed in VSMCs. RANKL directly stimulates osteogenic differentiation of VSMCs via a decrease in MGP and indirectly promotes osteogenesis via BMP2, which is part of the TGF-β superfamily, from ECs. Promoting osteogenic differentiation by RANKL in VSMCs leads to synthesis of bone proteins and matrix calcification within the arterial vessel

Fig. 2

Potential origin of cells that contribute to valve calcification and fibrosis. Valve interstitial cells (VICs) are the main cellular component of the aortic valve. In interstitial cells, activated myofibroblasts are likely to arise from either quiescent VICs or a subpopulation of endothelial cells that undergo endothelial to mesenchymal transformation (EMT). RANKL increased the matrix calcification, ALP activity, and activation of the osteoblast transcription factor runx2 in cultured human aortic valve myofibroblasts. OPG prevents the interaction of RANKL with its receptor, RANK

Fig. 3

Scheme of plaque calcification. Natural plaque progression involves lipid-pool expansion coupled with micro-calcifications within lipid pools. Micro-calcifications are also commonly found within an overlying fibrous cap. If these micro-calcifications coalesce into speckles and fragments during therapy or atheroma progression, vessel wall stresses may decrease significantly, contributing to plaque stability