Perspective on Dentoalveolar Manifestations Resulting From PHOSPHO1 Loss-of-Function: A Form of Pseudohypophosphatasia?

Fatma F Mohamed,José Luis Millán,Brian L Foster,Sonoko Narisawa,Flavia Amadeu De Oliveira,Colin Farquharson,Michael B Chavez

doi:10.3389/fdmed.2022.826387

Abstract

Mineralization of the skeleton occurs by several physicochemical and biochemical processes and mechanisms that facilitate the deposition of hydroxyapatite (HA) in specific areas of the extracellular matrix (ECM). Two key phosphatases, phosphatase, orphan 1 (PHOSPHO1) and tissue-non-specific alkaline phosphatase (TNAP), play complementary roles in the mineralization process. The actions of PHOSPHO1 on phosphocholine and phosphoethanolamine in matrix vesicles (MVs) produce inorganic phosphate (Pi) for the initiation of HA mineral formation within MVs. TNAP hydrolyzes adenosine triphosphate (ATP) and the mineralization inhibitor, inorganic pyrophosphate (PPi), to generate Pi that is incorporated into MVs. Genetic mutations in the ALPL gene-encoding TNAP lead to hypophosphatasia (HPP), characterized by low circulating TNAP levels (ALP), rickets in children and/or osteomalacia in adults, and a spectrum of dentoalveolar defects, the most prevalent being lack of acellular cementum leading to premature tooth loss. Given that the skeletal manifestations of genetic ablation of the Phospho1 gene in mice resemble many of the manifestations of HPP, we propose that Phospho1 gene mutations may underlie some cases of “pseudo-HPP” where ALP may be normal to subnormal, but ALPL mutation(s) have not been identified. The goal of this perspective article is to compare and contrast the loss-of-function effects of TNAP and PHOSPHO1 on the dentoalveolar complex to predict the likely dental phenotype in humans that may result from PHOSPHO1 mutations. Potential cases of pseudo-HPP associated with PHOSPHO1 mutations may resist diagnosis, and the dental manifestations could be a key criterion for consideration.

Highlights

Mineralization of skeleton occurs by several physicochemical and biochemical processes and mechanisms that facilitate the deposition of hydroxyapatite (HA) in specific areas of the extracellular matrix (ECM)
On the outer surface of the matrix vesicles (MVs) membrane, the glycosylphosphatidylinositol (GPI)anchored tissue-non-specific alkaline phosphatase (TNAP) isozyme hydrolyzes both adenosine triphosphate (ATP) and mineralization inhibitor inorganic pyrophosphate (PPi) to generate Pi that is incorporated into MVs by the action of phosphate transporter 1 (PiT-1) [6, 8]
Given that the symptomatology of Phospho1−/− mice resembles many of the manifestations of HPP, we propose that a subset of individuals with HPP-like manifestations that resist diagnosis could potentially carry unreported pathogenic PHOSPHO1 variants

Summary

INTRODUCTION

Mineralization of skeleton occurs by several physicochemical and biochemical processes and mechanisms that facilitate the deposition of hydroxyapatite (HA) in specific areas of the extracellular matrix (ECM). Given that the symptomatology of Phospho1−/− mice (osteomalacia, spontaneous fractures, scoliosis) resembles many of the manifestations of HPP, we propose that a subset of individuals with HPP-like manifestations that resist diagnosis (i.e., some in the pseudo-HPP group) could potentially carry unreported pathogenic PHOSPHO1 variants The goal of this perspective article is to compare and contrast the loss-of-function effects of key mineralization-associated phosphatases, TNAP and PHOSPHO1, on the dentoalveolar complex to predict the dental phenotype in humans that may result from PHOSPHO1 mutations. While enamel and dentin defects in mouse models of HPP are well-represented in reports on developmental phenotypes, the longer lifespan of cKO vs Alpl−/− mice allowed assessment of tissues later in life, leading to the first observation of severe periodontal bone loss in a mouse HPP model (yellow dotted lines showing alveolar crest height in Figures 1F vs 1H) Histology reveals that both Alpl−/− and cKO mouse models of HPP have prominent acellular cementum hypoplasia, resulting in the poor periodontal attachment (Figures 1K–N).

ETHICS STATEMENT

Findings

DATA AVAILABILITY STATEMENT