Renal calcium stones: insights from the control of bone mineralization.

Extracellular pyrophosphate (PPi) plays a central role in the control of normal bone mineralization since it antagonizes inorganic phosphate in the promotion of hydroxyapatite deposition. Studies using knock-out mice have established the functional importance of PPi generation via nucleotide pyrophosphatase phosphodiesterases (NPP) and of PPi transmembrane transport by the progressive ankylosis (ANK) protein. Tissue non-specific alkaline phosphatase activity counteracts this by hydrolysis of PPi to inorganic phosphate. The molecular nature and transport function of ANK are reviewed. A close parallel is drawn between the controlled mineralization of bone and the prevention of abnormal calcium crystal deposition within the kidney, especially when concentrated urine is produced. Pyrophosphate is present in urine, and ANK is expressed in the cortical collecting duct where PPi transport to both the tubular lumen and the renal interstitium may occur. Pyrophosphate may also be generated here by nucleoside triphosphate diphosphohydrolases (NTPD2 and 3) together with NPP1. Alkaline phosphatase activity is restricted to the proximal nephron, remote from these sites of PPi generation, transport and function. The physiological importance of PPi generation and transport in preventing idiopathic calcium renal stone disease and nephrocalcinosis now needs to be established.