Enzyme replacement prevents enamel defects in hypophosphatasia mice


Autoria(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.; Millan, Jose Luis
Contribuinte(s)

UNIVERSIDADE DE SÃO PAULO

Data(s)

05/11/2013

05/11/2013

2012

Resumo

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.

National Institutes of Health, USA [DE12889, AR47908, AR53102]

National Institutes of Health, USA

CAPES [4176-09-0]

CAPES

Identificador

JOURNAL OF BONE AND MINERAL RESEARCH, HOBOKEN, v. 27, n. 8, supl. 1, Part 1, pp. 1722-1734, AUG, 2012

0884-0431

http://www.producao.usp.br/handle/BDPI/41523

10.1002/jbmr.1619

http://dx.doi.org/10.1002/jbmr.1619

Idioma(s)

eng

Publicador

WILEY-BLACKWELL

HOBOKEN

Relação

JOURNAL OF BONE AND MINERAL RESEARCH

Direitos

restrictedAccess

Copyright WILEY-BLACKWELL

Palavras-Chave #METABOLIC BONE DISEASE #TEETH AND DENTAL APPLICATIONS #TREATMENTS #NONSPECIFIC ALKALINE-PHOSPHATASE #IN-VITRO #INFANTILE HYPOPHOSPHATASIA #MURINE HYPOPHOSPHATASIA #PERIODONTAL-LIGAMENT #CEMENTUM FORMATION #AMELOBLASTIN GENE #TISSUE #MATRIX #TEETH #ENDOCRINOLOGY & METABOLISM
Tipo

article

original article

publishedVersion