Disease relevance of PTH

• Active vitamin D compounds repress parathyroid hormone (PTH) gene transcription and block chief cell hyperplasia, making them integral tools in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease [1].
• Because neonatal bovine and pathological human parathyroid glands show cellular hyperplasia, we studied the temporal relationship between cellular proliferation and the regulation of PTH release and cytosolic calcium concentration in cultured bovine parathyroid cells [2].
• The PTH-related protein may have a role in the syndrome of humoral hypercalcemia of malignancy [3].
• These findings suggest that stage-dependent increases in PTH/PTH-related peptide receptor levels localize the hormone stimulation of proteoglycan synthesis and inhibition of precocious hypertrophy in the matrix-forming zone of growth plates [4].
• Pertussis toxin also increased PTH mRNA at a low extracellular Ca2+ concentration (0.7 mM) (4-fold increase) and a normal concentration (1.25 mM) (2-fold increase) [5].

High impact information on PTH

• Hypocalcemia and inhibition of parathyroid hormone secretion after administration of WR-2721 (a radioprotective and chemoprotective agent) [6].
• Our results indicate that parathyroid hormone rarely, if ever, causes hypercalcemia in malignant disease [7].
• Messenger RNA was prepared from cultured cell lines or tumors; active RNA fractions were hybridized with either human or bovine cloned parathyroid hormone DNA that had been labeled to a high specific activity with [32P]nucleotide [7].
• We conclude that WR-2721 inhibits the secretion of parathyroid hormone and enhances calciuria, thereby leading to hypocalcemia [6].
• Although the molecular nature of such ion sensors is unknown, parathyroid cells possess a cell surface Ca(2+)-sensing mechanism that also recognizes trivalent and polyvalent cations (such as neomycin) and couples by changes in phosphoinositide turnover and cytosolic Ca2+ to regulation of parathyroid hormone secretion [8].

Chemical compound and disease context of PTH

• Incubation with pertussis toxin (5 x 10(-9) M), which blocks the high-calcium-mediated inhibition of cyclic adenosine monophosphate accumulation in these cells, also reversed the inhibition of PTH mRNA levels at high Ca2+ (2.0 mM) with a marked increase in PTH mRNA levels [5].
• In this study, we evaluated the effects of 17 beta-estradiol and progesterone on PTH secretion from abnormal parathyroid tissue from seven patients (four adenomas, three hyperplasia) [9].
• Greater than 90% of tumor-bearing mice developed a syndrome of hypercalcemia, hypophosphatemia, hypercalciuria, elevated plasma 1,25-dihydroxyvitamin D, normal immunoreactive PTH, elevated urinary cAMP, and accelerated bone resorption compared to control mice [10].
• Dispersed bovine parathyroid cells treated with or without 0.5 micrograms/ml pertussis toxin were tested with stimulatory (epinephrine, isoproterenol) or inhibitory (PGF2 alpha) agonists for responses in cAMP accumulation (5-min incubation) or PTH (90-min incubation) release [11].
• Pertussis toxin produced an enhanced response to epinephrine (a mixed alpha-adrenergic and beta-adrenergic agonist) in cAMP production and in PTH secretion [11].

Biological context of PTH

• CONCLUSION: Our results identify a new protein-binding element in the PTH mRNA 3'-UTR [12].
• In bovine PTH mRNA, it is the only element, and it is functional in destabilizing a reporter gene [12].
• Therefore, different species have alternative cis-acting protein-binding elements that may determine the regulation of PTH mRNA stability in response to changes in serum calcium and phosphate [12].
• The data, therefore, highlight the likely involvement of the Sp family in regulating PTH gene expression through interactions with an Sp1 DNA element in the hormone's promoter [13].
• The structure of the bovine parathyroid hormone (PTH) gene has been analyzed by Southern blot hybridization of genomic DNA and by nucleotide sequence analysis of a cloned PTH gene [14].

Anatomical context of PTH

• Sp3/Sp1 in the parathyroid gland: identification of an Sp1 deoxyribonucleic acid element in the parathyroid hormone promoter [13].
• There was a close correlation between this progressive decrease in maximal inhibition of PTH release and the cytosolic calcium at high extracellular calcium in cultured cells (r = 0.99, P < 0.001) [2].
• B-cell tolerance to human PTH was broken by immunisation with PTH peptides in adjuvant [15].
• At later times of incubation (30-90 min), autoradiographic grains within the secretion glanules migrated to the periphery of the cell and to the plasma membrane, in correlation with the release of PTH first detected by 30 min [16].
• We conclude that proteolytic conversion of Pre-ProPTH to ProPTH takes place in the RER and that subsequent conversion of ProPTH to PTH occurs in the Golgi complex [16].

Associations of PTH with chemical compounds

• Inhibition of 1alphaOHase with the cytochrome P450 inhibitor clotrimazole did not block 25(OH)D(3)-mediated suppression of PTH [1].
• INTRODUCTION: In the rat, Ca(2+) and phosphate regulate PTH mRNA stability by the interaction of trans-acting proteins with a defined cis-acting instability element in the distal region of the PTH mRNA 3'-untranslated region (UTR) [12].
• The existence of PTH-sensitive adenylate cyclase and the reproduction of increased epithelial Ca transport by dibutyryl-cAMP suggest that cAMP is the mediator [17].
• Large amounts of PTH given to human subjects as serial injections or prolonged infusions cause decreased urinary 3',5'-cyclic adenosine monophosphate (cAMP) responses to subsequent PTH doses, but it is uncertain whether lower doses given over shorter periods similarly cause renal tachyphylaxis to PTH action [18].
• Combined treatment with 10(-6) M retinoic acid and 10(-8) M 1,25(OH)2D3 more effectively decreased PTH secretion and preproPTH mRNA than did either compound alone [19].

Regulatory relationships of PTH

• It is proposed that PTH influences Ca++ reabsorption by the DCT because the target molecule, the Na+/Ca++ exchanger, is located exclusively at this site [20].
• Atrial natriuretic peptide inhibited the basal and PTH-stimulated [3H]thymidine incorporation into DNA of chondroprogenitor cells, but did not affect avian skin fibroblast proliferation [21].
• The studies indicate that somatostatin inhibits PTH secretion by an action distal to cAMP generation [22].
• We conclude that PTH-rP is not secreted from parathyroid cells via the regulated pathway utilizing PTH secretory granules [23].
• Northern blot analysis revealed that parathyroid hormone-related protein (1-34) inhibited both basal and thrombin-induced endothelin-1 gene expression [24].

Other interactions of PTH

• Study of the peptides produced from each form of PTH by cleavage with cyanogen bromide showed that peak II is oxidized at methionine 8 and peak III at methionine 18 while peak I is oxidized at both methionines [25].
• 5. Inhibition of binding of tritiated hormone by unlabeled PTH was also highly effective at pH 6.0, but this apparently specific binding was also inhibited by adrenocorticotropic hormone, insulin, glucagon, and vasopressin [26].
• PTHrP (1-34) and PTH (1-34) dose-dependently inhibited BVSMC calcification [27].
• Incubation of DCT suspension with 10(-8) M bovine PTH (1-34) resulted in a significant increase in the Na(+)-dependent Ca++ uptake by the corresponding BLM vesicles [20].
• Using preparations of dispersed bovine parathyroid cells, we have investigated the effect of a 16-residue synthetic peptide, ARF-16, which corresponds to the N-terminus of the ADP-ribosylation factor, on the secretion of PTH [28].

Analytical, diagnostic and therapeutic context of PTH

• Metabolism of 25(OH)D(3) by bPTC was assessed using a radioimmunoassay that measures all 1-hydroxylated metabolites of vitamin D. 25(OH)D(3) suppressed PTH secretion and mRNA (ED(50)=2 nM), but was several hundred times less potent than 1,25(OH)(2)D(3) [1].
• Introduction by molecular cloning of artifactual inverted sequences at the 5' terminus of the sense strand of bovine parathyroid hormone cDNA [29].
• The sequence of bovine parathyroid hormone mRNA has been determined by sequence analysis of near full-length cloned DNA complementary to the mRNA [30].
• In the present study, we observed that all-trans- or 9-cis retinoic acid suppressed the release of PTH from bovine parathyroid cell cultures [19].
• To confirm that adequate stores of PTH were present, immunocytochemistry and in situ hybridization were performed [31].

References