title: Enzyme replacement prevents enamel defects in hypophosphatasia mice.
abstract: 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.
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Manisha C
authors.initials: MC
authors.lastname: Yadav
authors.forename: Rodrigo Cardoso
authors.initials: RC
authors.lastname: de Oliveira
authors.forename: Brian L
authors.initials: BL
authors.lastname: Foster
authors.forename: Hanson
authors.initials: H
authors.lastname: Fong
authors.forename: Esther
authors.initials: E
authors.lastname: Cory
authors.forename: Sonoko
authors.initials: S
authors.lastname: Narisawa
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sah
authors.forename: Martha
authors.initials: M
authors.lastname: Somerman
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millán
mesh_terms: D000469:Alkaline Phosphatase / Q000172:deficiency / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D003743:Dental Enamel / Q000000981:diagnostic imaging / Q000196:embryology / Q000201:enzymology / Q000473:pathology*; D056947:Enzyme Replacement Therapy; D006801:Humans; D007014:Hypophosphatasia / Q000517:prevention & control* / Q000628:therapy*; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007180:Incisor / Q000000981:diagnostic imaging / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008903:Minerals / Q000378:metabolism; D008963:Molar / Q000000981:diagnostic imaging / Q000473:pathology / Q000648:ultrastructure; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D055114:X-Ray Microtomography
chemical_list: D007074:Immunoglobulin G; D008903:Minerals; D011993:Recombinant Fusion Proteins; C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase; C570710:asfotase alfa