Physiological role of alkaline phosphatase explored in hypophosphatasia

Michael P. Whyte

Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review

261 Scopus citations


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.
Number of pages11
ISBN (Print)9781573317856
StatePublished - Mar 2010

Publication series

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


  • Ectoenzyme
  • Inorganic pyrophosphate
  • Osteomalacia
  • Rickets


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