**5. Inhibitors of vascular calcification**

Fetuin-A is originally synthesized in the liver, and circulating fetuin-A concentrations fall during the inflammatory process [48]. Fetuin-A is an extracellular calcium-regulatory factor that functions as a new inhibitor of calcium-phosphate deposition [49], suppresses calcinosis by binding hydroxyapatite [50], and protects VSMCs from the harmful effects of calcium overload and subsequent calcification [51]. Fetuin-A suppresses VSMC apoptosis through death-signaling pathways: (i) it is internalized by VSMCs, concentrated in intracellular vesicles, and secreted via vesicle release from apoptotic and living VSMCs; (ii) fetuin-A in vesicles suppresses their ability to nucleate calcium phosphate; and (iii) fetuin-A increases phagocytosis of vesicles by VSMCs. These results confirm finding that the internalization of fetuin-A into VSMCs is a key finding in the inhibition of vesicle-mediated VSMC calcification [51]. In *in vitro* experiments, fetuin-A has been reported to antagonize the action of TGF-*β*1 (transforming growth factor-β1) and inhibit osteogenesis and calcium-containing matrix deposition in dexamethasone-treated rat bone marrow cells [49]. Moreover, fetuin-A-KO mice show severe ectopic calcinosis in the myocardium, kidney, lung, tongue, and skin [49]. A recent study [49] demonstrated that ESRD patients who had lower serum fetuin-A concentrations showed a lower survival rate from cardiovascular diseases, indicating that fetuin-A is related to the mechanism of the accelerated extraskeletal calcinosis.

Matrix Gla protein (MGP) is a matrix protein that was firstly discovered from bone [52], and it is an important modulator of vascular calcification. To exert its biological activity, MGP requires to be activated through interaction with vitamin K [53]. The calcification of cartilage and blood vessels has been found to be inhibited by MGP [54]. MGP affects on vascular calcification directly by reducing calcium crystal formation and indirectly by modulating transcription factors that suppress VSMC transformation to the osteoblast-like cells [55]. Moreover, MGP is an important factor capable of transformation of VSMCs [58]. A decrease in glomerular filtration rate has been shown to result in a reduction in uncarboxylated MGP level which is related to vascular calcification [56].

The receptor activator of nuclear factor *κ*-light-chain-enhancer of activated B-cells (RANK), and RANK ligand (RANKL), and osteoprotegerin (OPG) might be associated with the mechanism of vascular calcification. RANKL functions are inhibited by OPG that acts as a decoy receptor to inhibit RANKL/RANK relationships [57]. This system may be related to the imbalance of bone–vascular calcification interactions and could be a predictor of the grade of vascular calcification. A recent study [58] demonstrated that coronary arterial calcification (CAC) is significantly associated with plasma OPG values in CKD patients. The serum OPG levels *>*757.7 pg/ml in CKD patients were indicator of CAC. These results are compatible with those reported in our previous study [59]. The relationship between serum OPG concentrations and CAC is unclear. The functional role of circulating OPG has been found to be modulated by several factors, including the relevant association of different tissue sources and the contribution of various comorbidities. OPG has been reported to have protective effect against vascular calcium deposition in experimental models [60]. Interestingly, higher OPG concentrations have been shown in patients with vascular injury, indicating that an elevated OPG concentration may be attribute to a compensatory selfdefense mechanism that stimulates vascular calcification [61].
