3.8 Article

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

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FRONTIERS IN DENTAL MEDICINE
卷 3, 期 -, 页码 -

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fdmed.2022.826387

关键词

hypophosphatasia; mineralization; dental; Periodontal; genetic models

资金

  1. This study was funded by the National Institute of Dental and Craniofacial Research (NIDCR) grants R01DE12889 to JM, R03DE028411 to BF, and T32DE014320 in support of MC, and research grants from Soft Bones, Inc. to BF and FA, and Biotechnology and Biologic [R03DE028411, T32DE014320, BB/J004316/1]
  2. National Institute of Dental and Craniofacial Research (NIDCR)
  3. Soft Bones, Inc.
  4. Biotechnology and Biological Sciences Research Council (BBSRC) for Institute Strategic Programme
  5. [R01DE12889]

向作者/读者索取更多资源

Mineralization of the skeleton requires the actions of phosphatases PHOSPHO1 and TNAP. PHOSPHO1 produces inorganic phosphate to initiate hydroxyapatite formation, while TNAP hydrolyzes substances to generate phosphate. Mutations in the Phospho1 gene may contribute to dental defects in pseudo-HPP cases.
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.

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