Dentoalveolar defects and impaired alveolar bone healing in a neural crest directed conditional knockout mouse model of hypophosphatasia

Abstract

Hypophosphatasia (HPP) is an inherited error-of-metabolism caused by loss-of-function mutations in ALPL-encoded tissue-nonspecific alkaline phosphatase (TNAP). HPP has wide-ranging severity, including a clinical subtype called odontohypophosphatasia (odonto HPP), which selectively affects craniofacial structures. Dentoalveolar defects in HPP can affect enamel, dentin, and alveolar bone, and deficient acellular cementum contributes to tooth loss. Global Alpl knockout phenocopies effects of severe HPP, but early lethality precludes longer-term studies. Aiming to create a mouse model replicating dentoalveolar effects of HPP, we used Wnt1^Cre2 mice to conditionally delete Alpl in ectomesenchymal cells that make dentin, cementum, periodontal ligament (PDL), and alveolar bone. We compared appendicular and craniofacial skeletal effects of Wnt1^Cre2 to Prx1^Cre conditional Alpl ablation in limb bud mesenchyme. We also tested alveolar bone socket healing in Wnt1^Cre2; Alpl^fl/fl conditional knockout mice and the effect of TNAP-Fc-D₁₀ enzyme replacement therapy (ERT) on socket healing. Prx1^Cre; Alpl^fl/fl mice exhibited 38 % reduced circulating alkaline phosphatase (ALP) and long bone defects, but no craniofacial phenotypes. Wnt1^Cre2; Alpl^fl/fl mice featured 60 % reduced ALP and profound mineralization defects in dentin, cementum, and alveolar bone, but no appendicular skeleton changes. Defects were noted in neural crest-derived intersphenoid synchondrosis of the cranial base and mandibular condyle of Wnt1^Cre2; Alpl^fl/fl mice. Extraction of maxillary molars in Wnt1^Cre2; Alpl^fl/fl mice revealed profound alveolar bone healing defects that were partially rescued by ERT. Cranial neural crest deletion of Alpl resulted in a mouse model phenocopying odonto HPP that can be used to investigate mechanisms underlying pathologies as well as interventions.

Keywords: Bone; Dentin; Hypophosphatasia; Mineralized tissue/development; Periodontium.