Physiological role of alkaline phosphatase explored in hypophosphatasia

Research output: Chapter in Book/Report/Conference proceedingConference contribution

208 Scopus citations

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 (PPi) 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 B6 metabolism in HPP revealed that TNSALP is an ectoenzyme. PPi excesses cause chondrocalcinosis and sometimes arthropathy. The skeletal disease is due to PPi 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.

Original languageEnglish
Title of host publicationSkeletal Biology and Medicine
PublisherBlackwell Publishing Inc.
Pages190-200
Number of pages11
ISBN (Print)9781573317856
DOIs
StatePublished - Mar 2010

Publication series

NameAnnals of the New York Academy of Sciences
Volume1192
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • Ectoenzyme
  • Inorganic pyrophosphate
  • Osteomalacia
  • Rickets

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    Whyte, M. P. (2010). Physiological role of alkaline phosphatase explored in hypophosphatasia. In Skeletal Biology and Medicine (pp. 190-200). (Annals of the New York Academy of Sciences; Vol. 1192). Blackwell Publishing Inc.. https://doi.org/10.1111/j.1749-6632.2010.05387.x