Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.26.9 (ribonuclease)
 6,589 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present work was to characterize at the molecular level the mechanism of PTH resistance in a rat model of secondary hyperparathyroidism resulting from vitamin D deprivation. PTH/PTH-related protein (PTHrp) receptor messenger RNA (mRNA) expression, assayed by ribonuclease protection analysis, was studied in the kidney, femoral epi/metaphysis, and diaphysis. In addition, in the kidney, PTH/PTHrp receptor mRNA expression was correlated to receptor function by measuring adenyl cyclase activity in crude renal membranes after stimulation by PTH (10(-10) - 10(-6) M), forskolin (0.1 and 0.2 mM), NaF (5 and 10 mM), and isoproterenol (1 and 10 microM). Four groups of rats were studied to investigate the effects of calcium, PTH, and/or vitamin D status. The first group received a control diet (D+D+). The second group received a diet deficient in vitamin D until death (D-D-). In the two other groups that also received a vitamin D-deficient diet, the hypocalcemia and the hyperparathyroidism were later corrected, by either vitamin D supplementation (D-D+) or lactose and high calcium diet (D-Ca+), 1 week before death. The results revealed a 2-fold decrease in the PTH-induced adenyl cyclase activity of the renal membranes in the D-D- rats compared to those in the three other groups. There was no significant difference in the four groups in adenyl cyclase activity stimulated by forskolin, NaF, and isoproterenol. The decrease in PTH-induced adenyl cyclase activity was associated with an approximately 2-fold increase in PTH/PTHrp receptor mRNA expression in the kidneys of the D-D- rats compared to controls. Normalization of PTH/PTHrp receptor mRNA expression was observed after vitamin D supplementation (D-D+ rats), but not after correction of the hypocalcemia and secondary hyperparathyroidism by oral lactose and calcium supplementation. In the epi/metaphysis, an approximately 2-fold increase in PTH/PTHrp receptor mRNA was also observed in the D-D- rats compared to the controls; this increase was partially corrected upon normalization of the calcemia and PTH levels with either vitamin D (D-D+ group) or lactose/calcium (D-Ca+ group). In the diaphysis, no change in the expression of PTH/PTHrp receptor mRNA was observed in any group.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Parathyroid hormone (PTH)/PTH-related protein receptor messenger ribonucleic acid expression and PTH response in a rat model of secondary hyperparathyroidism associated with vitamin D deficiency. 764 81

X-linked hypophosphatemia (XLH), a renal phosphate (Pi) wasting disorder with defective bone mineralization, is caused by mutations in the PHEX gene (a Pi-regulating gene with homology to endopeptidases on the X chromosome). Parathyroid hormone (PTH) status in XLH has been controversial, with the prevailing belief that hyperparathyroidism develops in response to Pi therapy. We report a 5-year-old girl with XLH (patient 1) who had significant hyperparathyroidism at presentation, prior to initiation of therapy. We examined her response to a single oral Pi dose, in combination with calcitriol, and demonstrated a rise in serum concentration of intact PTH, which peaked at 4 h and paralleled the rise in serum Pi concentration. We also present two other patients whose parathyroid glands were analyzed for PHEX mRNA expression following parathyroidectomy. Patient 2 had autonomous hyperparathyroidism associated with chronic renal insufficiency, and patient 3, with XLH, developed autonomous hyperparathyroidism after 8 years of therapy with Pi and calcitriol. Following parathyroidectomy, patient 3 exhibited an increase in both serum Pi concentration and renal Pi reabsorption. The abundance of PHEX mRNA, relative to beta-actin mRNA, in parathyroid glands from patients 2 and 3 was several-fold greater than that in human fetal calvaria, as estimated by ribonuclease protection assay. In summary, we have shown that hyperparathyroidism can be a primary manifestation of XLH and that PHEX is abundantly expressed in the parathyroid gland. Given that PHEX has homology to endopeptidases, we propose that PHEX may have a role in the normal regulation of PTH.
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PMID:PHEX expression in parathyroid gland and parathyroid hormone dysregulation in X-linked hypophosphatemia. 1046 May 13

Parathyroid bone disease in humans is caused by chronic hyperparathyroidism (HPT). Continuous infusion of PTH into rats results in histological changes similar to parathyroid bone disease, including increased bone formation, focal bone resorption, and severe peritrabecular fibrosis, whereas pulsatile PTH increases bone formation without skeletal abnormalities. Using a cDNA microarray with over 5000 genes, we identified an association between increased platelet-derived growth factor-A (PDGF-A) signaling and PTH-induced bone disease in rats. Verification of PDGF-A overexpression was accomplished with a ribonuclease protection assay. Using immunohistochemistry, PDGF-A peptide was localized to mast cells in PTH-treated rats. We also report a novel strategy for prevention of parathyroid bone disease using triazolopyrimidine (trapidil). Trapidil, an inhibitor of PDGF signaling, did not have any effect on indexes of bone turnover in normal rats. However, dramatic reductions in marrow fibrosis and bone resorption, but not bone formation, were observed in PTH-treated rats given trapidil. Also, trapidil antagonized the PTH-induced increases in mRNA levels for PDGF-A. These results suggest that PDGF signaling is important for the detrimental skeletal effects of HPT, and drugs that target the cytokine or its receptor might be useful in reducing or preventing parathyroid bone disease.
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PMID:Triazolopyrimidine (trapidil), a platelet-derived growth factor antagonist, inhibits parathyroid bone disease in an animal model for chronic hyperparathyroidism. 1269 8