To-date, the function of tissue-nonspecific
alkaline phosphatase (TNAP) has largely been defined through studies in patients and mice affected by
hypophosphatasia (
HPP), a rare inborn-error-of-metabolism caused by mutation(s) in the TNAP gene (ALPL). The skeletal disease in
HPP can be explained by alterations in the Pi/PPi ratio, with accumulation in the concentration of the mineralization inhibitor PPi as the culprit in preventing propagation of mineralization onto the collagenous extracellular matrix in bones and teeth. Accumulation of phosphorylated
osteopontin increases the severity of
HPP, at least in mice. Disruption in the metabolism of
vitamin B6 leads to intracellular deficiency of
pyridoxal, and this causes
vitamin B6-responsive
seizures in patients with the severe forms of the disease. Recent findings also implicate TNAP in the metabolism of
ATP, in the production of
adenosine and in the dephosphorylation of the
bacterial toxin lipopolysaccharide, all molecules known to be involved in
inflammation. The role of TNAP in establishing the
ATP/
adenosine ratio is important for purinergic signaling, and these mechanisms could be significant in determining axonal growth in the brain. Finally, the potential involvement of TNAP in dephosphorylating
tau protein and its role in the pathogenesis of
Alzheimer's disease is intriguing.