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Enzyme replacement prevents enamel defects in hypophosphatasia mice
Author(s) -
Yadav Manisha C,
de Oliveira Rodrigo Cardoso,
Foster Brian L,
Fong Hanson,
Cory Esther,
Narisawa Sonoko,
Sah Robert L,
Somerman Martha,
Whyte Michael P,
Millán José Luis
Publication year - 2012
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.1619
Subject(s) - hypophosphatasia , ameloblast , enamel paint , alkaline phosphatase , molar , endocrinology , amelogenesis imperfecta , chemistry , rickets , medicine , enamel organ , cementum , anatomy , dentin , pathology , dentistry , vitamin d and neurology , enzyme , biochemistry
Hypophosphatasia (HPP) is the inborn error of metabolism characterized by deficiency of alkaline phosphatase activity, leading to rickets or osteomalacia and to dental defects. HPP occurs from loss‐of‐function mutations within the gene that encodes the tissue‐nonspecific isozyme of alkaline phosphatase (TNAP). TNAP knockout ( Alpl −/− , aka Akp2 −/− ) mice closely phenocopy infantile HPP, including the rickets, vitamin B6‐responsive seizures, improper dentin mineralization, and lack of acellular cementum. Here, we report that lack of TNAP in Alpl −/− mice also causes severe enamel defects, which are preventable by enzyme replacement with mineral‐targeted TNAP (ENB‐0040). Immunohistochemistry was used to map the spatiotemporal expression of TNAP in the tissues of the developing enamel organ of healthy mouse molars and incisors. We found strong, stage‐specific expression of TNAP in ameloblasts. In the Alpl −/− mice, histological, µCT, and scanning electron microscopy analysis showed reduced mineralization and disrupted organization of the rods and inter‐rod structures in enamel of both the molars and incisors. All of these abnormalities were prevented in mice receiving from birth daily subcutaneous injections of mineral‐targeting, human TNAP at 8.2 mg/kg/day for up to 44 days. These data reveal an important role for TNAP in enamel mineralization and demonstrate the efficacy of mineral‐targeted TNAP to prevent enamel defects in HPP. © 2012 American Society for Bone and Mineral Research.