Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to unravel the mechanisms by which interleukin (IL)-10, a potent pleiotropic cytokine, modulates alveolar bone homeostasis in C57BL/6 wild-type (WT) and IL-10 knockout (IL-10 KO) mice, evaluated at 8, 24, and 48 wk of age. Interleukin-10 KO mice presented significant alveolar bone loss when compared with WT mice, and this was not associated with changes in leukocyte counts or bacterial load. The levels of expression of messenger RNA (mRNA) for tumor necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6, transforming growth factor-beta (TGF-beta), receptor activator of nuclear factor kappaB ligand (RANKL), osteoprotegerin (OPG), and matrix metalloproteinase 13 (MMP13) were similar between both strains, whereas a significant decrease of tissue inhibitor of metalloproteinase 1 (TIMP1) mRNA expression was found at 48 wk in IL-10 KO mice. The osteoblast markers core binding factor alpha1 (CBFA1) and type I collagen (COL-I) were expressed at similar levels in both strains, whereas the levels of alkaline phosphatase (ALP) and osteocalcin (OCN), and those of the osteocyte markers phosphate-regulating gene endopeptidases (PHEX) and dentin matrix protein 1 (DMP1) were significantly lower in IL-10 KO mice. Our results demonstrate that the alveolar bone loss in the absence of IL-10 was associated with a reduced expression of osteoblast and osteocyte markers, an effect independent of microbial, inflammatory or bone-resorptive pathways.
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PMID:Down-regulation of expression of osteoblast and osteocyte markers in periodontal tissues associated with the spontaneous alveolar bone loss of interleukin-10 knockout mice. 2015 61

X-linked hypophosphatemic rickets (XLH) is a dominantly inherited disease characterized by renal phosphate wasting, aberrant vitamin D metabolism, and defective bone mineralization. It is known that XLH in humans and in certain mouse models is caused by inactivating mutations in PHEX/Phex (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). By a genome-wide N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a dominant mouse mutation that exhibits the classic clinical manifestations of XLH, including growth retardation, skeletal abnormalities (rickets/osteomalacia), hypophosphatemia, and increased serum alkaline phosphatase (ALP) levels. Mapping and sequencing revealed that these mice carry a point mutation in exon 14 of the Phex gene that introduces a stop codon at amino acid 496 of the coding sequence (Phex(Jrt) also published as Phex(K496X) [Ichikawa et al., 2012]). Fgf23 mRNA expression as well as that of osteocalcin, bone sialoprotein, and matrix extracellular phosphoglycoprotein was upregulated in male mutant long bone, but that of sclerostin was unaffected. Although Phex mRNA is expressed in bone from mutant hemizygous male mice (Phex(Jrt)/Y mice), no Phex protein was detected in immunoblots of femoral bone protein. Stromal cultures from mutant bone marrow were indistinguishable from those of wild-type mice with respect to differentiation and mineralization. The ability of Phex(Jrt)/Y osteoblasts to mineralize and the altered expression levels of matrix proteins compared with the well-studied Hyp mice makes it a unique model with which to further explore the clinical manifestations of XLH and its link to FGF23 as well as to evaluate potential new therapeutic strategies.
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PMID:A novel Phex mutation in a new mouse model of hypophosphatemic rickets. 2257 57

We report the case of a 30-year-old African-American male with osteopetrosis and hypophosphatemia, presenting with diffuse myalgias. Laboratory evaluation performed revealed a low serum phosphorus level with urinary phosphate wasting, low calcium, and 25-hydroxyvitamin D concentrations, as well as elevated alkaline phosphatase. Skull and pelvic radiographs revealed high bone density consistent with high bone mass found on bone mineral density reports. PHEX gene mutation analysis was negative. Patient was started on calcium and phosphorus replacement, and he clinically improved. This paper will review the different subtypes of osteopetrosis, and the evaluation of hypophosphatemia.
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PMID:Osteopetrosis, hypophosphatemia, and phosphaturia in a young man: a case presentation and differential diagnosis. 2293 98

X-linked hypophosphatemia (XLH) is caused by mutations in the PHEX gene, which increase circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Because XLH is a dominant disease, one mutant allele is sufficient for manifestation of the disease. However, the dosage effect of a PHEX mutation in XLH is not completely understood. To examine the effect of Phex genotypes, we compared serum biochemistries and skeletal measures between all five possible genotypes of a new murine model of XLH (Phex (K496X) or Phex (Jrt) ). Compared to sex-matched littermate controls, all Phex mutant mice had hypophosphatemia, mild hypocalcemia, and increased parathyroid hormone and alkaline phosphatase levels. Furthermore, mutant mice had markedly elevated serum Fgf23 levels due to increased Fgf23 expression and reduced cleavage of Fgf23. Although females with a homozygous Phex mutation were slightly more hypocalcemic and hypophosphatemic than heterozygous females, the two groups had comparable intact Fgf23 levels. Similarly, there was no difference in intact Fgf23 or phosphorus concentrations between hemizygous males and heterozygous females. Compared to heterozygous females, homozygous counterparts were significantly smaller and had shorter femurs with reduced bone mineral density, suggesting the existence of dosage effect in the skeletal phenotype of XLH. However, overall phenotypic trends in regards to mineral ion homeostasis were mostly unaffected by the presence of one or two mutant Phex allele(s). The lack of a gene dosage effect on circulating Fgf23 (and thus phosphorus) levels suggests that a Phex mutation may create the lower set point for extracellular phosphate concentrations.
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PMID:Dosage effect of a Phex mutation in a murine model of X-linked hypophosphatemia. 2370 Jan 48

Bone is mineralized when hydroxyapatite crystals derived from calcium ions and inorganic phosphate (Pi) grow along collagen fibrils in the extracellular matrix. Mineralization is initiated by nucleation of those crystals. Mature osteoblasts secrete matrix vesicles into osteoid, which contain growing hydroxyapatite crystal seeds. After rupture of the lipid bilayer of those vesicles, crystals continue to grow as a mineralized nodule and adhere to collagen fibrils. It remains controversial whether nucleation occurs mainly in matrix vesicles or also extra-vesicularly around collagen fibrils. Mineralization is inhibited by pyrophosphate (PPi) and by SIBLING family proteins, which carry an acidic serine- and aspartate-rich motif (ASARM) and include osteopontin, dentin matrix protein 1 and MEPE. Intracellular and extracellular activity of these factors is regulated by the PPi-generating ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) , the PPi-transporter progressive ankylosis (ANK) protein, the PPi-degrading/Pi-generating ectoenzyme alkaline phosphatase (ALPL, TNAP) , and PHEX endopeptidase. Gain- or loss-of-function mutations in genes encoding these proteins are associated with mineralization disorders such as ectopic calcification and other pathologies.
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PMID:[Updates on rickets and osteomalacia: mechanism and regulation of bone mineralization]. 2407 44

X-linked hypophosphatemia (XLH) is the most common form of familial hypophosphatemic rickets and it is caused by loss-of-function mutations in the PHEX gene. Recently, a wide variety of PHEX gene defects in XLH have been revealed; these include missense mutations, nonsense mutations, splice site mutations, insertions, and deletions. Recently, we encountered a 2-year-9-month-old female with sporadic hypophosphatemic rickets. She underwent osteotomy, dental abscess was evident, and there was severe bowing of the legs. A low serum phosphorus level in combination with elevated serum alkaline phosphatase activity and normal serum calcium is suggestive of hypophosphatemic rickets. PHEX gene analysis revealed a splice acceptor site mutation, c.934-1G>T (IVS8(-1)G>T), at the intron8 and exon9 junction. To the best of our knowledge, this mutation is novel and has not been reported. The results of this study expand and improve our understanding of the clinical and molecular characteristics and the global pool of patients with sporadic hypophosphatemic rickets.
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PMID:A novel de novo mutation within PHEX gene in a young girl with hypophosphatemic rickets and review of literature. 2492 62

Mutations in phosphate-regulating gene (PHEX) lead to X-linked hypophosphatemic rickets (XLH), a genetic disease characterized by impaired mineralization in bones and teeth. In human XLH tooth dentin, calcospherites that would normally merge as part of the mineralization process are separated by unmineralized interglobular spaces where fragments of matrix proteins accumulate. Here, we immunolocalized osteopontin (OPN) in human XLH teeth, in a three-dimensional XLH human dental pulp stem cell-collagen scaffold culture model and in a rat tooth injury repair model treated with acidic serine- and aspartate-rich motif peptides (ASARM). In parallel, matrix extracellular phosphoglycoprotein (MEPE) immunolocalization and alkaline phosphatase (ALP) activity were assessed in XLH teeth. OPN was expressed by odontoblasts in the XLH models, and localized to the abnormal calcospherites of XLH tooth dentin. In addition, ALP activity and MEPE localization were abnormal in human XLH teeth, with MEPE showing an accumulation in the unmineralized interglobular spaces in dentin. Furthermore, XLH odontoblasts failed to form a well-polarized odontoblast layer. These data suggest that both MEPE and OPN are involved in impaired tooth mineralization associated with XLH, possibly through different effects on the mineralization process.
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PMID:Abnormal osteopontin and matrix extracellular phosphoglycoprotein localization, and odontoblast differentiation, in X-linked hypophosphatemic teeth. 2515 86

X-linked hypophosphatemia (XLH) is a skeletal disease caused by inactivating mutations in the PHEX gene. Mutated or absent PHEX protein/enzyme leads to a decreased serum phosphate level, which cause mineralization defects in the skeleton and teeth (osteomalacia/odontomalacia). It is not yet altogether clear whether these manifestations are caused solely by insufficient circulating phosphate availability for mineralization or also by a direct, local intrinsic effect caused by impaired PHEX activity. Here, we evaluated the local role of PHEX in a 3-dimensional model of extracellular matrix (ECM) mineralization. Dense collagen hydrogels were seeded either with human dental pulp cells from patients with characterized PHEX mutations or with sex- and age-matched healthy controls and cultured up to 24 d using osteogenic medium with standard phosphate concentration. Calcium quantification, micro-computed tomography, and histology with von Kossa staining for mineral showed significantly lower mineralization in XLH cell-seeded scaffolds, using nonparametric statistical tests. While apatitic mineralization was observed along collagen fibrils by electron microscopy in both groups, Raman microspectrometry indicated that XLH cells harboring the PHEX mutation produced less mineralized scaffolds having impaired mineral quality with less carbonate substitution and lower crystallinity. In the XLH cultures, immunoblotting revealed more abundant osteopontin (OPN), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE) than controls, as well as the presence of fragments of these proteins not found in controls, suggesting a role for PHEX in SIBLING protein degradation. Immunohistochemistry revealed altered OPN and DMP1 associated with an increased alkaline phosphatase staining in the XLH cultures. These results are consistent with impaired PHEX activity having local ECM effects in XLH. Future treatments for XLH should target both systemic and local manifestations.
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PMID:Defective Mineralization in X-Linked Hypophosphatemia Dental Pulp Cell Cultures. 2888 Jul 15

Background Hypophosphatemic rickets, including familial hypophosphatemic vitamin D-resistant rickets, which commonly manifests in childhood, is generally hereditary. X-linked dominant hypophosphatemic rickets (XLH, MIM307800), caused by inactivating mutations in the PHEX gene, is the most common form. This study aimed to identify the gene mutations responsible for three cases of XLH and its clinical phenotype. Methods We conducted a genetic diagnosis and clinical phenotypic linkage analysis of three pedigrees with XLH. Three probands finally diagnosed as XLH were analyzed by next-generation sequencing (NGS). Sanger sequencing was used for mutation scanning in other family members. Results For the three patients with XLH, the age of onset ranged from 1.5 to 2 years and their heights were less than three standard deviations (SDs) below the median. The patients exhibited curved deformities in both lower limbs, hypophosphatemia, elevated serum FGF23 levels and elevated levels of blood alkaline phosphatase, with normal levels of blood parathyroid hormone (PTH) and calcium. X-ray analysis of the limbs and chest revealed characteristic rickets signs. Three candidate pathogenic mutations were identified in PHEX (NM_000444.5): c.433G>T (p.Glu145*, p.E145*) in exon 4, c.1735G>A (p.Gly579Arg, p.G579R) (rs875989883) in exon 17 and c.2245T>C (p.Trp749Arg, p.W749R) in exon 22. The nonsense mutation (p.E145*) in PHEX is novel and is predicted to cause a truncation of the encoded protein, resulting in loss of function. Conclusions The novel nonsense mutation (p.E145*) in PHEX is possibly involved in inherited XLH.
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PMID:Genetic analysis of three families with X-linked dominant hypophosphatemic rickets. 2985 4

Osteocytes play a key role in orchestrating bone homeostasis and turnover and, therefore, in vitro investigations with osteocytes are of high relevance for biomaterial and drug testing in future. In this study, collagen type I gels and collagen gels modified with biomimetically mineralized collagen were tested as three-dimensional (3D) environment for the maintenance of the osteocytic phenotype of primary human osteocytes. After cultivation in different collagen gels, cells were analyzed microscopically for the osteocytic phenotype and gene expression of osteocyte marker genes osteocalcin, podoplanin (PDPN)/E11, phosphate regulating endopeptidase homolog, X-linked (PHEX), matrix extracellular phosphoglycoprotein (MEPE), dentin matrix protein 1 (DMP-1), and sclerostin (SOST). Directly after isolation from bone tissue the cells expressed all examined osteocyte markers. After 7 days of 3D cultivation in collagen gels the osteocytic marker genes MEPE and SOST were upregulated and the other marker genes still expressed. Modification of collagen gels with biomimetically mineralized collagen and strontium-doped mineralized collagen prevented the cell-seeded gels from shrinking. Osteocyte morphology was not affected by the gel modification. However, the isolation of RNA from the mineralized gel variants was heavily impaired. Alternatively, the osteocytic differentiation of human osteoblasts in the different collagen gels was examined. Primary human osteoblasts were embedded into the gels and cultivated under osteogenic stimulation. After 14 days of cultivation, embedded osteoblasts showed osteocyte-like morphology and positive staining for DMP-1. Early osteocyte marker genes, such as PDPN/E11 and PHEX, were expressed while the expression of the osteoblast marker gene alkaline phosphatase (ALPL) increased. This ALPL upregulation was partly prevented by modification of collagen gels with mineralized collagen. Impact Statement This research focuses on the in vitro three-dimensional cultivation of primary human osteocytes instead of rodent osteocyte cell lines. Stable in vitro cultures of these regulating cells provide the opportunity to establish co- and triple cultures with osteoblasts and osteoclasts to analyze the cross talk between these cell species and to establish in vitro bone models for the testing of bioactive molecules, growth factors, drugs, and biomaterials.
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PMID:Primary Human Osteocyte Networks in Pure and Modified Collagen Gels. 3064 77


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