Physiological role of alkaline phosphatase explored in hypophosphatasia
- 5 April 2010
- journal article
- review article
- Published by Wiley in Annals of the New York Academy of Sciences
- Vol. 1192 (1), 190-200
- https://doi.org/10.1111/j.1749-6632.2010.05387.x
Abstract
Hypophosphatasia (HPP) is the instructive rickets or osteomalacia caused by loss-of-function mutation(s) within TNSALP, the gene that encodes the "tissue nonspecific" isoenzyme of alkaline phosphatase (TNSALP). HPP reveals a critical role for this enzyme in skeletal mineralization. Increased extracellular levels of pyridoxal 5'-phosphate and inorganic pyrophosphate (PP(i)) demonstrate that TNSALP is a phosphomonoester phosphohydrolase and a pyrophosphatase that hydrolyzes much lower concentrations of natural substrates than the artificial substrates of laboratory assays. Clearly, TNSALP acts at physiological pH and "alkaline phosphatase" is a misnomer. Aberrations of vitamin B(6) metabolism in HPP revealed that TNSALP is an ectoenzyme. PP(i) excesses cause chondrocalcinosis and sometimes arthropathy. The skeletal disease is due to PP(i) inhibition of hydroxyapatite crystal growth extracellularly so that crystals form within matrix vesicles but fail to enlarge after these structures rupture. Trials of alkaline phosphatase replacement therapy for HPP suggest that TNSALP functions at the level of skeletal tissues.Keywords
This publication has 31 references indexed in Scilit:
- Enzyme Replacement Therapy for Murine HypophosphatasiaJournal of Bone and Mineral Research, 2008
- Perinatal lethal hypophosphatasia; Clinical, radiologic and morphologic findingsPediatric Radiology, 1991
- Hypophosphatasia and the Extracellular Metabolism of Inorganic Pyrophosphate: Clinical and Laboratory Aspects: Part ICritical Reviews in Clinical Laboratory Sciences, 1991
- Perinatal hypophosphatasia: tissue levels of vitamin B6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5'-phosphate. Evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase.JCI Insight, 1988
- Structural and Functional Roles of Glycosyl-Phosphatidylinositol in MembranesScience, 1988
- Markedly increased circulating pyridoxal-5'-phosphate levels in hypophosphatasia. Alkaline phosphatase acts in vitamin B6 metabolism.JCI Insight, 1985
- Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusions of alkaline phosphatase-rich Paget plasma: Results in three additional patientsThe Journal of Pediatrics, 1984
- HypophosphatasiaMedicine, 1984
- Hydrolysis of pyridoxal-5'-phosphate in plasma in conditions with raised alkaline phosphate.Gut, 1980
- VESICLES ASSOCIATED WITH CALCIFICATION IN THE MATRIX OF EPIPHYSEAL CARTILAGEThe Journal of cell biology, 1969