Artículos de revistas
Enzyme replacement prevents enamel defects in hypophosphatasia mice
Fecha
2012Registro en:
JOURNAL OF BONE AND MINERAL RESEARCH, HOBOKEN, v. 27, n. 8, supl. 1, Part 1, pp. 1722-1734, AUG, 2012
0884-0431
10.1002/jbmr.1619
Autor
Yadav, Manisha C.
de Oliveira, Rodrigo Cardoso
Foster, Brian L.
Fong, Hanson
Cory, Esther
Narisawa, Sonoko
Sah, Robert L.
Somerman, Martha
Whyte, Michael P.
Millan, Jose Luis
Institución
Resumen
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, mu CT, 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. (C) 2012 American Society for Bone and Mineral Research.