Hypophosphatasia and How Alkaline Phosphatase Promotes Mineralization

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23 Scopus citations

Abstract

Hypophosphatasia (HPP) is the remarkably informative inborn error of metabolism and metabolic bone disease that features low serum alkaline phosphatase (ALP) activity (hypophosphatasemia) due to loss-of-function mutation(s) of TNSALP (ALPL), the gene that encodes the "tissue nonspecific" (bone/liver) isoenzyme of ALP (TNSALP). Lessons from HPP revealed that TNSALP is a cell-surface phosphohydrolase and showed how it functions. Several phosphocompounds that are TNSALP natural substrates accumulate extracellularly in HPP, including inorganic pyrophosphate (PPi), an inhibitor of hydroxyapatite (HA) crystal growth, and pyridoxal 5-phosphate (PLP), the major circulating form of vitamin B6. The superabundance of extracellular PPi blocks mineralization of the skeleton after matrix vesicles (MVs) rupture and release their nascent HA crystals. This causes rickets or osteomalacia despite normal or sometimes elevated circulating levels of calcium and phosphorus and adequate vitamin D. Failure of the cementumcovering tooth roots to mineralize leads to premature exfoliation of deciduous teeth. However, HPP spans the greatest range of severity of all skeletal diseases. This is largely explained by autosomal dominant (AD) and autosomal recessive (AR) inheritance from among several hundred, typically missense, mutations of TNSALP. Unless treated, perinatal HPP kills rapidly due to profound skeletal hypomineralization. Infantile HPP presents postnatally, but before age 6 months with rickets, failure-to-thrive, and sometimes hypercalcemia or vitamin B6-dependent seizures. Progressive chest deformity often causes lethal pulmonary problems. When severe, childhood HPP features symptomatic rickets, premature loss of deciduous teeth, and chronic muscle weakness. Adult HPP typically presents in middle age with osteomalacia and pseudofractures and sometimes arthropathies involving PPi deposition. Odonto-HPP, likely the most prevalent HPP, features tooth loss without skeletal disease. AR inheritance accounts for the most severely affected patients, whereas AD and rarely AR transmission explain the mild forms. In 2015, substantially effective bone-targeted TNSALP replacement therapy (asfotase alfa) received regulatory approval multinationally, typically for pediatric-onset HPP-the last rickets/osteomalacia to await a medical treatment. Now, for a variety of disorders, excessive ALP activity in diseased tissues is implicated in ectopic mineralization.

Original languageEnglish
Title of host publicationGenetics of Bone Biology and Skeletal Disease
Subtitle of host publicationSecond Edition
PublisherElsevier Inc.
Pages481-505
Number of pages25
ISBN (Electronic)9780128041987
ISBN (Print)9780128041826
DOIs
StatePublished - Jan 1 2018

Keywords

  • Calcification
  • Chondrocalcinosis
  • Enzymopathy
  • Hydroxyapatite
  • Hypercalcemia
  • Hyperphosphatemia
  • Inborn-error-of-metabolism
  • Inorganic pyrophosphate
  • Matrix vesicle
  • Mineralization
  • Osteomalacia
  • Phosphoethanolamine
  • Pyridoxal phosphate
  • Rickets
  • Vitamin B

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