Abstract
Hypophosphatasia (HPP) results from ALPL mutations leading to deficient activity of the tissue-non-specific alkaline phosphatase isozyme (TNAP) and thereby extracellular accumulation of inorganic pyrophosphate (PPi), a natural substrate of TNAP and potent inhibitor of mineralization. Thus, HPP features rickets or osteomalacia and hypomineralization of teeth. Enzyme replacement using mineral-targeted TNAP from birth prevented severe HPP in TNAP-knockout mice and was then shown to rescue and substantially treat infants and young children with life-threatening HPP. Clinical trials are revealing aspects of HPP pathophysiology not yet fully understood, such as craniosynostosis and muscle weakness when HPP is severe. New treatment approaches are under development to improve patient care.
Highlights
In 1923, Robert Robison, Ph.D. discovered a phosphatase abundant in the skeleton possibly to generate inorganic phosphate (Pi) required to form bone mineral [1]
Hypophosphatasia (HPP) results from ALPL mutations leading to deficient activity of the tissue-nonspecific alkaline phosphatase isozyme (TNAP) and thereby extracellular accumulation of inorganic pyrophosphate (PPi), a natural substrate of TNAP and potent inhibitor of mineralization
Only a few [inorganic pyrophosphate (PPi), pyridoxal 50-phosphate (PLP), and likely phosphoethanolamine (PEA)] are natural substrates for TNAP based on studies of HPP patients and fibroblasts and Alpl knockout (KO) mice [28, 29]
Summary
In 1923, Robert Robison, Ph.D. discovered a phosphatase abundant in the skeleton possibly to generate inorganic phosphate (Pi) required to form bone mineral [1]. In 1932, he postulated that an additional but unknown factor regulates skeletal mineralization [2]. This factor would prove to be inorganic pyrophosphate (PPi), a potent inhibitor of mineralization and natural substrate for Robison’s enzyme [3]. The efficacy of enzyme replacement therapy (EzRT) using a mineral-targeted form of recombinant TNAP has been demonstrated for severe HPP [9]. Our review summarizes knowledge concerning TNAP, including revelations about its physiological function coming from investigation of HPP patients and mouse models and successes using EzRT
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