Tissue Non-Specific Alkaline Phosphatase and Vascular Calcification: A Potential Therapeutic Target

Abstract

Vascular calcification is a pathologic phenomenon consisting of calcium phosphate crystal deposition in the vascular walls. Vascular calcification has been found to be a risk factor for cardiovascular diseases, due to its correlation with cardiovascular events and mortality, and it has been associated with aging, diabetes, and chronic kidney disease. Studies of vascular calcification have focused on phosphate homeostasis, primarily on the important role of hyperphosphatemia. Moreover, vascular calcification has been associated with loss of plasma pyrophosphate, one of the main inhibitors of calcification, thus indicating the importance of the phosphate/pyrophosphate ratio. Extracellular pyrophosphate can be synthesized from extracellular ATP by ecto-nucleotide pyrophosphatase/ phosphodiesterase, whereas pyrophosphate is hydrolyzed to phosphate by tissuenonspecific alkaline phosphatase, contributing to the formation of hydroxyapatite crystals. Over the last decade, vascular calcification has been the subject of numerous reviews and studies, which have revealed new agents and activities that may aid in explaining the complex physiology of this condition. This review summarizes current knowledge about alkaline phosphatase and its role in the process of vascular calcification as a key regulator of the phosphate/pyrophosphate ratio.

Keywords: CKD; TNAP; Vascular calcification; aging; alkaline phosphatase; hemodialysis; pyrophosphate..

Fig. (1)

Schematic representation of tissue non-specific alkaline phosphatase. Each monomer contains an active site (metal binding site) where phosphorus binds, and a calcium binding site. The calcium and metal union site allow interactions with Ca, Mg or Zn, which are necessary for the enzyme to express activity. The two monomers are connected in the crowd domain by flexible sequences of each. Both monomers are anchors to the membrane via GPI motifs.

Fig. (2)

Role of TNAP in the extracellular pyrophosphate metabolism. ATP is released by cells via exocytotic mechanisms and through multiple types of membrane channels. Ectonucleotide pyrophosphatase phosphodiesterase (eNPP) hydrolyzes ATP, releasing pyrophosphate (PPi) and adenosine-5’-monophosphate (AMP). PPi is degraded to phosphate (Pi) by tissue non-specific alkaline phosphatase (TNAP). AMP is degraded to adenosine (Ado) and Pi via ecto-5´nucleotidase (5NT). Ado and Pi are recovered from the extracellular space by equilibrative nucleoside transporter 1 (ENT1) and sodium phosphate transporter (NaPi), respectively. ATP is generated in the mitochondria or through another metabolic pathway.