Vascular calcification is a complex, regulated process that involves the molecular interplay between calcification stimulators and inhibitors. Although numerous individual molecules and/or factors have been identified as stimulators of calcification, including inorganic phosphate, calcium, sodium-phosphate cotransporters, Runx2, tissue non-specific alkaline phosphase (TNAP), glucose, acetylated LDL, tumor necrosis factor-alpha (TNF-α), and bone morphogenetic protein 2 (BMP-2) 18–20
, their exact mechanism to induce vascular calcification and their interaction with the calcification inhibitors is not yet clearly understood.
Recent studies have shed some light on vascular calcification and how a disrupted balance between calcification inhibiting and promoting factors can lead to calcification. As mentioned, there are several key factors that have been shown to directly regulate the induction and progression of vascular calcification; these include but are not limited to circulating factors (i.e., phosphate, calcium, pyrophosphate, parathyroid hormone: PTH) and their signaling components, matrix molecules (i.e., Matrix Gla Protein: MGP), and catalyzing enzymes (i.e., TNAP).
Serum phosphate and calcium levels are important determinants of vascular calcification, as inadequate regulation of these minerals can lead to spontaneous deposition of calcium-phosphate in the blood vessels and soft tissues. Hyperphosphatemia in dialysis patient correlates with vascular calcification and effective phosphate control with noncalcium phosphate binders is correlated with attenuated progression of vascular calcification in these patients 21
. In addition, in vitro
studies have shown that smooth muscle cells grown in the in the presence of elevated inorganic phosphorus undergo a dramatic phenotypic change characterized by the downregulation of smooth muscle cell lineage genes and the upregulationof the osteochondrogenic lineage genes 22
. Similar to phosphorus, a positive calcium balance is linked to vascular calcification in humans 23
. In vitro
, calcium promotes mineralization in vascular smooth muscle cell and the calcium-induced mineralization upregulates the expression of the major sodium-dependent phosphate cotransporters in these cells 24
Inorganic pyrophosphate inhibits vascular calcification by restricting hydroxyapatite formation and propagation through its biophysical chelator-like role, as well as stabilizing the aortic phenotype by acting as a paracrine regulator 19
. Reduced plasma pyrophosphate levels are reported in hemodialysis patients and are exacerbated as a result of pyrophosphate clearance 25
. It is therefore likely that restoring pyrophosphate levels may help in limiting vascular calcification. Another factor, TNAP, an enzyme produced in several tissues including bones, serves as a functional phenotypic marker of osteoblasts and is often used as a molecular marker for vascular calcification. Since pyrophosphate is a substrate for TNAP and phosphorus is the product of its catalytic activity, one can theoretically anticipate that upregulated TNAP expression acts as a precursor to vascular calcification 26
. PTH can also influence vascular calcification. Uncontrolled secretion of PTH can release excessive amount of calcium form bone, which can precipitate as calcifying foci in blood vessels and soft tissue 27
BMP-2 plays a role in calcification by exerting osteogenic effects on blood vessels and soft tissues 28
. Studies have shown a positive correlation between BMP2 and vascular calcification. Furthermore, matrix proteins, like MGP can inhibit vascular calcification. A positive correlation exists between the local expression of MGP and calcification in arteries. In MGP knockout mice and human Keutel Syndrome, the deficiency of MGP, are associated with ectopic calcification 29
. MGP is able to control vascular calcification partly through its Gla residues, which have a calcium/hydroxyl apatite chelating capacity.
Vascular calcification is histologically divided into four main types: 1) atherosclerotic intimal calcificaiton, 2) medial artery calcification (Monckeberg sclerosis), 3) cardiac valve calcificaiton, and 4) arteriole calcification in the form of calciphylaxis. Although systemic factors have great importance in inducing calcification, the interplay between the resident cells of the vasculature usually determines the extent of the damage; cross talks and phenotypic alteration of endothelial cells, smooth muscle cells, pericytes and perhaps mesenchymal stem cells, in response to systemic dysregulation of mineral balance can significantly influence the calcification process. In general, there are significant similarities between skeletal mineralization and vascular and soft tissue calcification 28
. The reader is referred to recent reviews for an in-depth overview of the general aspects of bone and vascular calcification 18,28
. The purpose of this review is to briefly discuss the potential effects of FGF23-klotho activity on the development of vascular and soft tissue calcification.