Asunto(s)
Acondroplasia/epidemiología , Enfermedades del Desarrollo Óseo/congénito , Enfermedades del Desarrollo Óseo/genética , Acondroplasia/tratamiento farmacológico , Fosfatasa Alcalina/efectos de los fármacos , Fosfatasa Alcalina/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Desarrollo Óseo , Enfermedades del Desarrollo Óseo/diagnóstico por imagen , Enfermedades del Desarrollo Óseo/epidemiología , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Hipofosfatasia/tratamiento farmacológico , Hipofosfatasia/prevención & control , Inmunoglobulina G/uso terapéutico , Terapia Molecular Dirigida/métodos , Fenotipo , Radiografía/métodos , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
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.