Figure 3.

The reciprocal interaction between the different ecto-nucleotidases. The downward and upward arrow represents, respectively, a deficiency and overexpression of the ecto-nucleotidase activity. (Blue) NPP1 and NPP3 are involved in the synthesis and hydrolysis of pyrophosphate (PP_i). Either a deficiency or overexpression of NPP1 activity leads to arterial calcification, as well as overexpression of NPP1 favoring TNAP activity and inducing less ATP mediated purinergic receptor 2 signaling (P2R). (Green) A deficiency of TNAP activity is linked to neurological defects and fracture risk by decreased P_i generation, while overexpression of TNAP activity favors arterial calcification through a reduction in PP_i. (Orange) A deficiency of CD73 or 5′-nucleotidase triggers arterial calcification by promoting TNAP activity and reducing the production of adenosine and thus less adenosine mediated P1R signaling. (Red) Inhibition of NTPDase 1 reduces arterial calcification by diminishing P_i generation. This scheme is based on the results in multiple cell types including VSMCs, VICs and endothelial cells but also i.e., primary dermal fibroblasts from arterial calcifications due to deficiency of 5′-nucleotidase/CD73 (ACDC) patients.