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

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.

Gene Therapy Using Recombinant AAV Type 8 Vector Encoding TNAP‐D10 Improves the Skeletal Phenotypes in Murine Models of Osteomalacia

“…(19,68) Given that the symptomatology of Phospho1 À/À mice resembles many of the manifestations of HPP, we surmised that Phos-pho1 gene mutations could be associated with cases of pseudo-HPP, where TNAP may be normal to subnormal, but an ALPL mutation has not been identified. (11) Overexpressing TNAP under control of the ApoE promoter, in the Phospho1 À/À mice did not prevent the skeletal defect in that model but ablating Spp1 (osteopontin [OPN]) in the Phospho1 À/À mice helped improve the skeletal phenotype. (69) We concluded that although Alpl and Phospho1 deficiencies lead to similar skeletal phenotypes and a parallel increase in the plasma levels of PP i and OPN, there was an apparent dissociation in the hierarchical roles of these potent inhibitors of mineralization, with elevated PP i and elevated OPN levels causing the respective skeletal phenotypes in Alpl À/À and Phospho1 À/À mice.…”

“…Here we show that, indeed, the use of AAV8‐TNAP‐D 10 prevents severe scoliosis that characterizes this murine model with improvements in the trabecular bone and a reduced marrow space in the vertebrae of AAV8‐TNAP‐D 10 ‐treated Phospho1 −/− mice. In a recent perspective, ( 11 ) we discussed 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. These patients would be expected to have skeletal defects such as osteomalacia and fractures consistent with HPP but featuring dental phenotypes with mild enamel and dentin effects and intact cementum, periodontal attachment, and no premature tooth loss.…”

“…Studies in PHOSPHO1deficient mice (Phospho1 À/À ) display elevated PP i levels and decreased plasma TNAP activity (9)(10)(11) and present skeletal abnormalities, including fractures, bowed long bones, osteomalacia, and scoliosis in the early stage of life that resemble HPP, and thus are here referred to as a model of pseudo-HPP. (11)(12)(13) The pathophysiology of rickets/osteomalacia and dental disease in HPP and Phospho1 À/À mice can be explained by the accumulation in the extracellular matrix of PP i , a potent mineralization inhibitor (14) and one of the natural substrates of TNAP. (15)(16)(17) Asfotase alfa, a recombinant form of TNAP (sALP-Fc-D 10 ) that contains the Fc region of immunoglobulin (Fc) and a deca-aspartate (D 10 ) mineral-targeting motif (18) was shown efficacious in extending life and preventing skeletal and dental disease in a mouse model of severe infantile HPP.…”

“…Studies in PHOSPHO1‐deficient mice ( Phospho1 −/− ) display elevated PP i levels and decreased plasma TNAP activity ( 9 , 10 , 11 ) and present skeletal abnormalities, including fractures, bowed long bones, osteomalacia, and scoliosis in the early stage of life that resemble HPP, and thus are here referred to as a model of pseudo‐HPP. ( 11 , 12 , 13 ) The pathophysiology of rickets/osteomalacia and dental disease in HPP and Phospho1 −/− mice can be explained by the accumulation in the extracellular matrix of PP i , a potent mineralization inhibitor ( 14 ) and one of the natural substrates of TNAP. ( 15 , 16 , 17 )…”