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

Tissue-nonspecific alkaline phosphatase (TNAP) is a key enzyme responsible for skeletal tissue mineralization. It is involved in the dephosphorylation of various physiological substrates, and has vital physiological functions, including extra-skeletal functions, such as neuronal development, detoxification of lipopolysaccharide (LPS), an anti-inflammatory role, bile pH regulation, and the maintenance of the blood brain barrier (BBB). TNAP is also implicated in ectopic pathological calcification of soft tissues, especially the vasculature. Although it is the crucial enzyme in mineralization of skeletal and dental tissues, it is a logical clinical target to attenuate vascular calcification. Various tools and studies have been developed to inhibit its activity to arrest soft tissue mineralization. However, we should not neglect its other physiological functions prior to therapies targeting TNAP. Therefore, a better understanding into the mechanisms mediated by TNAP is needed for minimizing off targeted effects and aid in the betterment of various pathological scenarios. In this review, we have discussed the mechanism of mineralization and functions of TNAP beyond its primary role of hard tissue mineralization.