Review Article

Pathophysiological and Genetic Aspects of Vascular Calcification

Table 1

Summary of vascular calcification mediators and their potential functions in promoting calcification.

ProteinGeneFunctionCalcification

IL-1βIL1B (interleukin 1 beta)Proinflammatory cytokine which promotes vascular calcification via NF-κB and Wnt signaling pathwayIntima/media
IL-6IL6 (interleukin 6)Proinflammatory cytokine which promotes vascular calcification through inflammation-induced oxidative stress.Intima/media
TNFα (tumor necrosis factor alpha)TNF (tumor necrosis factor)Inflammatory cytokine which promotes vascular calcification by increasing the expression of osteogenic genes.Intima/media
CRPCRP (C-reactive protein)Proinflammatory protein may contribute to vascular calcification through the raised expression of osteogenic factors such as Runx2 and TNAP.Intima/media
TNAP (tissue nonspecific alkaline phosphatase)ALPL (gene encoding human TNAP)Degrades inorganic pyrophosphate which makes VSMCs susceptible to calcificationMedia
Cbfa1/RUNX2 (RUNX family transcription factor 2)RUNX2 (RUNX family transcription factor 2)Transcription factor involved in chondrocyte and osteoblast differentiationMedia
OsterixSP7 (Sp7 transcription factor)Controls the osteoblast differentiation and bone formationMedia
BMP-2 (bone morphogenetic protein 2)BMP2 (bone morphogenetic protein 2)Osteogenic and osteoblast proliferation factor which upregulates the expression of Runx2Media
OsteocalcinBGLAP (bone gamma-carboxyglutamate protein)Protein derived from osteoblasts, which stimulates the PI3K/Akt signaling pathway and upregulating the nuclear factor-kappa β (NF-кβ)Media
RANKL (receptor activator of nuclear factor kappa-B ligand)>TNFS11 (TNF superfamily member)Regulates osteoclast differentiation and activationMedia/intima
RANK (receptor activator of nuclear factor kappa-B)TNFRSF11A (TNF receptor superfamily member 11a)Activates the transcription factor NF-κB for the generation and survival of osteoclastsMedia/intima
NF-κBNFKB (NF-kappa-B protein complex: NFKB1, NFKB2, RELA, RELB, and REL)Transcription factor which promotes vascular calcification through the expression of MSX2 (which increases TNAP expression) and reduces the expression of ANKH through the expression of tritetraprolineMedia/intima
Wnt/β-cateninWNT1/CTNNB1 (Wnt family member 1/catenin beta 1)Through its canonical pathway promotes osteogenic gene expression via nuclear β-catenin dependent transcriptionMedia
PTX3PTX3 (pentraxin 3)It has been reported that PTX3 induces the expression of RANKL by human osteoblasts, thereby promoting osteoclastogenesis in vitro culture systemMedia
Inorganic pyrophosphatePrevents the nucleation of amorphous calcium phosphate and inhibits hydroxyapatite crystallizationMedia
ANKHANKH (ankylosis, progressive homolog)Inhibits mineralization by exporting inorganic pyrophosphate to the extracellular space to inhibit hydroxyapatite formationMedia
Matrix gla proteinMGP (matrix gla protein)Inhibits vascular mineralization by binding to calcium ionsMedia
Fetuin AAHSG (alpha 2-HS glycoprotein)Inhibitor of calcification by binding to calcium ions and forming calciprotein particles (CCPs) which prevent the precipitation of amorphous calcium phosphate particlesMedia
OsteoprotegerinTNFRSF11B (TNF receptor superfamily member 11b)Binds to RANKL as a decoy receptor resulting in down regulation of osteoclast differentiation, which decreases osteoclast activityMedia/intima
DKK1 (Dickkopf Wnt signaling pathway inhibitor 1)DKK1 (Dickkopf Wnt signaling pathway inhibitor 1)Inhibitor of the canonical β-catenin-dependent Wnt pathway, it was shown to reduce the expression of Runx2 which is a canonical Wnt targetMedia
LRP5/6 (LDL receptor-related protein 5/6)LRP5/6 (LDL receptor-related protein 5/6)Wnt coreceptors that upon activation lead to stabilization of cytoplasm β-catenin, nuclear translocation, and target gene expressionMedia
SclerostinSOST (sclerostin)Inhibitor of Wnt/β-catenin signaling, decreases bone formation by inhibiting osteoblastogenesis, in osteoclasts, and enhances bone resorptionMedia
OsteopontinSPP1 (secreted phosphoprotein 1)Inhibitor of mineralization and ectopic calcification linking the extracellular matrix with calciumMedia