Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease

Abstract

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.

BMP-2 Long-Term Stimulation of Human Pre-Osteoblasts Induces Osteogenic Differentiation and Promotes Transdifferentiation and Bone Remodeling Processes

“…In our experiments, RUNX2 expression was highest at 14 days and decreased at later time points, which is consistent with data from other studies, as RUNX2 decreases as maturation proceeds [ 33 , 34 ]. ALP was increased after BMP-2 exposure, indicating an initiated mineralization process of the bone cells [ 35 ]. However, the generated data did not show a RUNX2 -mediated increased expression of COL1A1 , which encodes the pro-alpha 1 chain of type I collagen, a highly relevant protein in the extracellular matrix formation in bone.…”

Tissue Nonspecific Alkaline Phosphatase Function in Bone and Muscle Progenitor Cells: Control of Mitochondrial Respiration and ATP Production

“…Given that we investigated TNAP function in cultured Sol8 muscle progenitor cells, our results indicate a direct influence of TNAP on muscle progenitor cells that is likely mediated by mitochondrial changes. TNAP is also known to influence neural progenitor cells, development, and function [39,40]; therefore, it is also possible that TNAP deficiency causes loss of muscle strength, increased fatigue, and loss of motor coordination due to TNAP deficiency in neurons. TNAP regulates purinergic transmission in the central nervous system, and plays an important role in neuronal development, differentiation, and synaptic function [41].…”

The Physiological and Pathological Role of Tissue Nonspecific Alkaline Phosphatase beyond Mineralization

“…Patients with a severe life-threatening form of HPP also showed substantial improvement in bone mineralization and survival. In humans and mice models of HPP, the TNAP-deficient EVs’ extracellular growth of HA crystals is blocked by excessive extracellular accumulation of PP i [ 112 ]. Combined ablation of PHOSPHO1 and TNAP results in the absence of HA crystals within EVs, absence of skeletal mineralization and embryonic deadliness [ 113 ].…”

“…PHOSPHO1 is essential for P i generation within MVs which is necessary for the initiation of HA formation inside the vesicle. TNAP is a crucial PPiase essential for the extracellular growth of HA by supplying P i via PP i hydrolysis [ 112 ]. Ecto-Nucleotide Pyrophosphatase/ Phosphodiesterase-1 (NPP1), a cell surface enzyme on EVs is a potent ATPase which produces PPi and acts as a phosphatase in the absence of TNAP [ 115 ].…”