Summary Tissue-nonspecific alkaline phosphatase (TNAP) and PHOSPHO1 are two matrix vesicles (MVs)-associated enzymes critically important for the proper mineralization of skeletal and dental tissues. Inactivating mutations in the TNAP gene (ALPL in humans and Alp/ in mice) lead to hypophosphatasia (HPP) while ablation of the Phospho1 gene in mice leads to osteomalacia, fractures and early-onset scoliosis. The simultaneous ablation of Alp/ and Phospho1 lead to embryonic lethality characterized by complete absence of skeletal and dental mineralization. The significance of TNAP for biomineralization has been exploited therapeutically. Our laboratory has contributed much of the pre-clinical data validating mineral-targeted TNAP (asfotase alfa) for the treatment of HPP and approved in 2015 for pediatric-onset HPP. Since our demonstration that PHOSPHO1 deficiency in mice also leads to a soft bone phenotype not unlike HPP, a patient with PHOSPHO1 mutations displaying HPP like symptomatology has been identified. No treatment has yet been devised for this pseudo-HPP skeletal/dental disease and in this high-risk high-reward R21 application we propose to explore the potential therapeutic use of mineral-targeted TNAP to improve the skeletal and dental phenotype in our murine model of PHOSPHO1 deficiency.