Alkaline Phosphatase Knock-Out Mice Recapitulate the Metabolic and Skeletal Defects of Infantile Hypophosphatasia

Fedde, Kenton N.; Blair, Libby A.; Silverstein, Julie; Coburn, Stephen P.; Ryan, Lawrence M.; Weinstein, Robert S.; Waymire, Katrina G.; Narisawa, Sonoko; Millán, José Luis; MacGregor, Grant R.; Whyte, Michael P.

doi:10.1359/jbmr.1999.14.12.2015

Cited by 358 publications

(332 citation statements)

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“…Our studies point to circulating phosphate, rather than locally deposited phosphate, as a key determinant of hypertrophic chondrocyte apoptosis, because impaired apoptosis is observed when there is still marked von Kossa staining (indicating mineralization) of the late hypertrophic chondrocyte layer. Studies in the tissue-nonspecific alkaline phosphatase (TNAP) knockout mouse, a model for the human disorder hypophosphatasia, support this hypothesis (31). The absence of alkaline phosphatase impairs mineral deposition, thus despite normal circulating mineral ion levels, the TNAPnull mice have decreased skeletal mineralization.…”

Section: Discussionmentioning

confidence: 99%

Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes

Sabbagh

Carpenter

Demay

2005

Proc. Natl. Acad. Sci. U.S.A.

232

171

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Rickets is seen in association with vitamin D deficiency and in several genetic disorders associated with abnormal mineral ion homeostasis. Studies in vitamin D receptor (VDR)-null mice have demonstrated that expansion of the late hypertrophic chondrocyte layer, characteristic of rickets, is secondary to impaired apoptosis of these cells. The observation that normalization of mineral ion homeostasis in the VDR-null mice prevents rachitic changes suggests that rickets is secondary to hypocalcemia, hypophosphatemia, or hyperparathyroidism, rather than impaired VDR action. To determine which of these abnormalities is responsible for impaired chondrocyte apoptosis and subsequent rachitic changes, two additional models were examined: diet-induced hypophosphatemia͞hypercalcemia and hypophosphatemia secondary to mutations in the Phex gene. The former model is associated with suppressed parathyroid hormone levels as a consequence of hypercalcemia. The latter model demonstrates normal calcium and parathyroid hormone levels, but 1,25-dihydroxyvitamin D levels that are inappropriately low for the degree of hypophosphatemia. Our studies demonstrate that normal phosphorus levels are required for growth plate maturation and implicate a critical role for phosphate-regulated apoptosis of hypertrophic chondrocytes via activation of the caspase-9-mediated mitochondrial pathway. (2). Rachitic growth plates also are associated with inherited mutations that impair the actions of the Phex gene (X-linked hypophosphatemic rickets) (3, 4) and the metabolism of FGF-23 (autosomal dominant hypophosphatemic rickets) (5). Both of these disorders are associated with reduced 25-hydroxyvitamin D 1-␣-hydroxylase activity, leading to a reduction in 1,25(OH) 2 D synthesis. It was, therefore, unclear whether the pathophysiologic abnormality leading to rachitic growth plates in the hereditary hypophosphatemias is similar to that underlying rickets due to VDR deficiency and whether these rachitic changes are a direct consequence of impaired 1,25(OH) 2 D action.Targeted ablation of the VDR in mice is a phenocopy of the human disease hereditary vitamin D resistant rickets (6). These mice are born metabolically normal, but as a consequence of impaired 1,25(OH) 2 D-dependent intestinal calcium absorption, they develop hypocalcemia and secondary hyperparathyroidism, the latter of which leads to an increase in urinary phosphate excretion resulting in hypophosphatemia. The VDR-null mice develop rickets and osteomalacia by the fourth week of life. Investigations addressing the cellular basis for these rachitic changes demonstrate that the growth-plate abnormality in the VDR-null mice is due to an expansion of the late hypertrophic chondrocyte layer, a consequence of impaired apoptosis of these cells. Chondrocyte proliferation and acquisition of markers of chondrocyte differentiation as proliferative chondrocytes mature are unaffected by VDR ablation, as is signaling for vascular invasion assessed by VEGF mRNA expression (7). Of note, prevention of abnormal ...

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Section: Discussionmentioning

confidence: 99%

Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes

Sabbagh

Carpenter

Demay

2005

Proc. Natl. Acad. Sci. U.S.A.

232

171

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“…The generation and characterization of the Akp2 KO mice has been reported (22,23). These Akp2 KO mice were hybrids of C57BL͞6 ϫ 129͞J mouse strains.…”

Section: Methodsmentioning

confidence: 99%

Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization

Hessle

Johnson

Anderson

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

779

629

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I n the process of bone formation, osteoblasts mineralize the matrix by promoting the seeding of basic calcium phosphate crystals of hydroxyapatite in the sheltered interior of shed membrane-limited matrix vesicles (MVs) and by propagating hydroxyapatite mineral onto the collagenous extracellular matrix (osteoid; refs. 1 and 2). Tissue-nonspecific alkaline phosphatase (TNAP), an isozyme of a family of four homologous human alkaline phosphatase genes (3), plays a role in bone matrix mineralization. Deactivating mutations in the TNAP gene causes the inborn error of metabolism known as hypophosphatasia (4), characterized by poorly mineralized cartilage (rickets) and bones (osteomalacia), spontaneous bone fractures, and elevated extracellular inorganic pyrophosphate (PP i ) concentrations (5). The severity and expressivity of hypophosphatasia depends on the nature of the TNAP mutation (6). TNAP is present in MVs (7), and it has been proposed that the inorganic phosphate (P i )-generating activity of TNAP is required to generate the P i needed for hydroxyapatite crystallization (8-10). However, the ability of TNAP to hydrolyze PP i also has been hypothesized to be important to promote osteoblastic mineralization (11, 12), because PP i suppresses the formation and growth of hydroxyapatite crystals (13). In fact, heritable extracellular PP i deficiencies are models of ectopic calcification such as ankylosing spinal hyperostosis and pathologic soft-tissue ossification (14-16). PP i is produced by the nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity of a family of isozymes that include PC-1, B10͞PDNP3, and autotaxin (17-19). However, PC-1 seems to be the only NTPPPH present in MVs (20). TNAP knockout (KO) mice (21-23) recapitulate the heritable metabolic disease hypophosphatasia (5), whereas PC-1-null mice display hypermineralization abnormalities similar to cartilage calcification in osteoarthritis (14) and ossification of the posterior longitudinal ligament of the spine (15).We previously identified PC-1 as the likely NTPPPH isozyme to act on the same pathway with TNAP as antagonistic regulators of extracellular PP i concentrations (20). In this paper, we have tested the hypothesis that bone abnormalities caused by the lack of TNAP could be counterbalanced by the removal of PC-1 and vice versa. We show that bone mineralization in double-KO mice lacking both TNAP and PC-1 is essentially normal, providing evidence that TNAP and PC-1 are key regulators of bone mineralization by determining the normal steady-state levels of PP i . Our work suggests that TNAP and PC-1 may be useful therapeutic targets for the treatment of bone mineralization abnormalities. Materials and MethodsAkp2 and Enpp1 KO Mice. The generation and characterization of the Akp2 KO mice has been reported (22,23). These Akp2 KO mice were hybrids of C57BL͞6 ϫ 129͞J mouse strains. The generation of the Enpp1 KO mice has been reported briefly (24). These Enpp1 KO mice were hybrids of C57BL͞6 ϫ 129͞SvTerJ mouse strains. Akp2͞Enpp1 double-heterozy...

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“…Accordingly, mutations in the TNAP gene that cause impairment or loss of functional activity lead to hypophosphatasia in humans [486,487]. Similarly, TNAP knockout mice (Akp2−/−) accumulate extracellular PP i , reveal hypomineralization [488][489][490][491], and can serve as a model for the infantile form of hypophosphatasia [492]. The defect can be eliminated by subcutaneous injections of soluble TNAP targeted to mineralizing tissue [493,494] or by lentiviral application of a bone-targeted form of TNAP [495].…”

Section: Substrates and Catalytic Propertiesmentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

888

922

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Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

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Alkaline Phosphatase Knock-Out Mice Recapitulate the Metabolic and Skeletal Defects of Infantile Hypophosphatasia

Cited by 358 publications

References 37 publications

Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes

Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes

Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization

Cellular function and molecular structure of ecto-nucleotidases

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