Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in PHEX, a phosphate-regulating gene with homology to endopeptidases on the X chromosome, are responsible for X-linked hypophosphatemia (XLH). The murine Hyp homologue has the phenotypic features of XLH and harbors a large deletion in the 3' region of the Phex gene. We characterized the developmental expression and tissue distribution of Phex protein, using a monoclonal antibody against human PHEX, examined the effect of the Hyp mutation on Phex expression, and compared neprilysin (NEP), osteocalcin, and parathyroid hormone/parathyroid hormone-related protein (PTH/PTHrP) receptor gene expression in bone of normal and Hyp mice. Phex encodes a 100- to 105-kDa glycoprotein, which is present in bones and teeth of normal mice but not Hyp animals. These results were confirmed by in situ hybridization (ISH) and ribonuclease protection assay. Phex protein expression in femur and calvaria decreases with age, suggesting a correlation between Phex expression and bone formation. Immunohistochemical studies detected Phex protein in osteoblasts, osteocytes, and odontoblasts, but not in osteoblast precursors. In contrast to Phex, the abundance of NEP messenger RNA (mRNA) and protein is not significantly altered in Hyp bone. Similarly, osteocalcin and PTH/PTHrP receptor gene expression are not compromised in bone of Hyp mice. Our results are consistent with the hypothesis that loss of Phex function affects the mineralizing activity of osteoblasts rather than their differentiation.
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PMID:Developmental expression and tissue distribution of Phex protein: effect of the Hyp mutation and relationship to bone markers. 1093 42

Mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) are responsible for X-linked hypophosphataemia, and studies in the Hyp mouse model of the human disease implicate the gene product in the regulation of renal phosphate (P(i)) reabsorption and bone mineralization. Although the mechanism for PHEX action is unknown, structural homologies with members of the M13 family of endopeptidases suggest a function for PHEX protein in the activation or degradation of peptide factors involved in the control of renal P(i) transport and matrix mineralization. To determine whether PHEX has endopeptidase activity, we generated a recombinant soluble, secreted form of human PHEX (secPHEX) and tested the activity of the purified protein with several peptide substrates, including a variety of bone-related peptides. We found that parathyroid-hormone-related peptide(107-139) is a substrate for secPHEX and that the enzyme cleaves at three positions within the peptide, all located at the N-terminus of aspartate residues. Furthermore, we show that osteocalcin, PP(i) and P(i), all of which are abundant in bone, are inhibitors of secPHEX activity. Inhibition of secPHEX activity by osteocalcin was abolished in the presence of Ca(2+). We suggest that PHEX activity and mineralization may be controlled in vivo by PP(i)/P(i) and Ca(2+) and, in the latter case, the regulation requires the participation of osteocalcin.
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PMID:Characterization of PHEX endopeptidase catalytic activity: identification of parathyroid-hormone-related peptide107-139 as a substrate and osteocalcin, PPi and phosphate as inhibitors. 1131 Nov 33

Inactivating mutations of Phex, a phosphate-regulating endopeptidase, cause hypophosphatemia and impaired mineralization in X-linked hypophosphatemia (XLH) and its mouse homologue, Hyp. Because Phex is predominantly expressed in bone and cultured osteoblasts from Hyp mice display an apparent intrinsic mineralization defect, it is thought that reduced expression of Phex in mature osteoblasts is the primary cause of XLH. To test this hypothesis, we studied both targeted expression of Phex to osteoblasts in vivo under the control of the mouse osteocalcin (OG2) promoter and retroviral mediated overexpression of Phex in Hyp-derived osteoblasts (TMOb-Hyp) in vitro. Targeted overexpression of Phex to osteoblasts of OG2 Phex transgenic Hyp mice normalized Phex endopeptidase activity in bone but failed to correct the hypophosphatemia, rickets, or osteomalacia. OG2 Phex transgenic Hyp mice did exhibit a small, but significant, increase in bone mineral density and dry ashed weight, suggesting a partial mineralization effect from restoration of Phex function in mature osteoblasts. Similarly, retroviral mediated overexpression of Phex in TMOb-Hyp osteoblasts restored Phex mRNA levels, protein expression, and endopeptidase activity but failed to correct their intrinsic mineralization defect. In addition, we failed to detect the Phex substrate FGF-23 in osteoblasts. Taken together, these in vivo and in vitro data indicate that expression of Phex in osteoblasts is not sufficient to rescue the Hyp phenotype and that other sites of Phex expression and/or additional factors are likely to be important in the pathogenesis of XLH.
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PMID:Overexpression of Phex in osteoblasts fails to rescue the Hyp mouse phenotype. 1171 45

The Hyp mouse is a murine homolog of human X-linked hypophosphatemic rickets and displays hypo-mineralization in bone and dentin due to a defect of the phosphate-regulating gene with homology to endopeptidase on the X chromosome (Phex) gene. It has long been considered that the bone and dentin defects in Hyp mice are caused by hypophosphatemia alone, however, several recent studies have indicated the possibility that intrinsic defects are present in Hyp mice osteoblasts. Further, we previously found a hyper-expression of osteocalcin (OC) mRNA in Hyp mouse odontoblasts and suggested the possibility of the presence of intrinsic defects. In the present study, we evaluated morphological features and OC mRNA expression levels in tooth germs of Nor mice with a normal phex gene and a low concentration of serum phosphate, and compared them to those in Hyp and wild-type mice. Nor mice exhibited low serum phosphate levels, however, did not show the characteristic features of dentin defects seen in Hyp mice, such as widened predentin and hyper-expression of OC mRNA. These results suggest that the hypo-mineralization of dentin in Hyp mice is not dependent on serum phosphate level, but rather is affected by intrinsic defects in odontoblasts.
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PMID:Dentinal defects in Hyp mice not caused by hypophosphatemia alone. 1600 44

Aortic valve stenosis (AS) is the most common heart valve disease in North America and Europe leading to an increased risk of heart failure and death. A multidisciplinary evaluation of symptoms, individual risk profile, echocardiographic parameters, biomarkers assessment is required for an appropriate clinical and therapeutic management of AS. The natriuretic peptides (NPs) represent an important biomarker for diagnostic, prognostic and therapeutic purposes in several cardiovascular diseases. The present review article provides an overview of the current knowledge on the role of NPs in the pathogenesis, diagnosis, risk stratification and potential therapeutic implications in AS. C-type natriuretic peptide (CNP) level is reduced in AS, favoring the formation of calcified aggregates and an increased expression of bone-related transcripts and proteins (Runx2, osteonectin, osteocalcin, alkaline phospahatase). Consistent results were obtained through the inhibition of the type A and B natriuretic peptide receptors (NPRA, NPRB) and of the proprotein convertase furin expression. Increased plasma B-type natriuretic peptide (BNP) level contributes to monitor the progression of AS and to identify patients who would most benefit from an early therapeutic intervention, such as surgical or transcatheter aortic valve replacement. Moreover, a risk stratification of AS patients that takes into account the NPs level has a major impact toward the occurrence of heart failure, syncope and sudden cardiac death. Finally, the development of novel therapeutic strategies, such as the neprilysin inhibition, may represent a suitable pharmacological approach for the treatment of AS. Due to the above mentioned multiple roles, NPs represent key players in AS development, management and treatment.
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PMID:Molecular and clinical implications of natriuretic peptides in aortic valve stenosis. 3087 94