Disease relevance of PTH

• The data provide one possible pathway for the participation of excess PTH in the genesis of the anemia of uremia [1].
• Less severe vitamin D deficiency causes an increase of serum PTH leading to bone resorption, osteoporosis and fractures [2].
• Immunohistochemically, there were two different types of adenoma cells, i.e., one positive only for PTH and the other positive for both PTH and PTHrP [3].
• Furthermore, the PTH 1-84 secretory response to EGTA-induced acute and severe hypocalcemia was significantly inhibited by PTH 7-84 [4].
• To address this issue in humans, bone biopsy specimen samples from 9 normal controls and 16 patients with moderate to severe secondary renal hyperparathyroid bone disease (2 degrees HPT) with elevated PTH levels were studied to determine whether osteoclasts in the bone microenvironment express PTH-1R messenger RNA (mRNA) and protein [5].
• While hypoparathyroidism develops after TT plus ND, little is known of postoperative PTH response [6].

Psychiatry related information on PTH

• In general, there were no significant differences in anthropometrical variables, physical activity, dietary calcium, serum 25(OH)D, or PTH among genotype groups [7].
• Chromosome 22q11 deletion syndrome was first suspected at age 32 yr, based on the findings of subtle dysmorphic facial features and a history of learning disability in a patient with PTH-deficient hypocalcemia [8].
• In addition, the serum PTH level was also significantly higher in patients displaying C allele, as compared with the T/T group in the latter [9].
• Effect of smoking and smoking cessation on bone mass, bone remodeling, vitamin D, PTH and sex hormones [10].
• With this study, the authors investigated parathyroid hormone (PTH) behaviour in thirteen selected patients with alcohol abuse, free from any clinical or humoral sign of hepatopathy, and in ten healthy subjects as a control group [11].

High impact information on PTH

• These include changes in the taste perception of calcium, signals related to blood calcium concentrations, and actions of the primary hormones of calcium homeostasis: parathyroid hormone, calcitonin, and 1,25-dihydroxyvitamin D [12].
• We identified a mutant PTH/PTHrP type I receptor (PTHR1) in human enchondromatosis that signals abnormally in vitro and causes enchondroma-like lesions in transgenic mice [13].
• BACKGROUND: Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown [14].
• As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points [14].
• Serum osteocalcin and parathyroid hormone and urinary N-telopeptide, cortisol, and calcium excretion were measured serially [15].

Chemical compound and disease context of PTH

• During recovery from hypocalcemia, plasma Ca(2+) levels were significantly lower in the PTH 7-84-treated group, as compared with the vehicle group, and at the same time plasma PTH 1-84 levels were significantly suppressed [4].
• Clonal rat osteogenic sarcoma cells were used (UMR 106-06 line) which respond to PTH with an increase in cyclic AMP (cAMP) formation [16].
• The native plasma of patients suffering from renal insufficiency inhibited the parathyroid hormone (PTH), the vasopressin (VP) and the NaF-activated adenylate cyclase (AC) in bovine renal plasma membranes [17].
• We investigated in humoral hypercalcemia of malignancy whether parathyroid hormone-related protein (PTHrP) elevation causes a rise in 1,25-dihydroxyvitamin D (1,25-(OH)2 D) serum levels [18].
• We have now extended these studies to investigate the actions of androgens on hPTH-stimulated accumulation of cAMP, and on the roles of new protein synthesis and pertussis toxin (PTox) substrates in the actions of steroid hormones on SaOS-2 cells [19].

Biological context of PTH

• PTH-rP appears to have similar effects to those of PTH on the skeleton, the kidney, and overall calcium homeostasis [20].
• These patients have excess blood levels of parathyroid hormone (PTH) and it is possible that PTH inhibits erythropoiesis [1].
• Thus, PTH responsiveness of the RANKL gene is determined by a distant regulatory region that responds to cAMP in a cell-type-specific manner and Runx2 may contribute to such cell-type specificity [21].
• Vitamin D supplementation to vitamin D-deficient elderly suppresses serum PTH, increases bone mineral density and may decrease fracture incidence especially in nursing home residents [2].
• However, these inhibitors of second messenger dependent kinases had little effect on the later phase of PTH-stimulated ERK1/2 phosphorylation [22].

Anatomical context of PTH

• Expression of RANKL mRNA in osteoblasts/stromal cells is up-regulated by osteotropic factors such as 1 alpha, 25(OH)2D3, PTH, and IL-11 [23].
• Intact PTH (1-84 bPTH) in concentrations (7.5-30 U/ml;) comparable to those found in blood of uremic patients produced marked and significant (P less than 0.01) inhibition of BFU-E and mouse marrow GFU-GM, but not of mouse marrow CFU-E [1].
• In osteoblasts, RANKL expression is regulated by two major calcemic hormones, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and parathyroid hormone (PTH), as well as by several inflammatory/osteoclastogenic cytokines; the molecular mechanisms for this regulation are unclear [24].
• Primary hyperparathyroidism is a common endocrine disorder caused by parathyroid gland enlargement and excessive parathyroid hormone (PTH) secretion [25].
• NCD14+ monocytes also differentiated into osteoclasts in PTH-treated cocultures with SaOS-4/3 cells [26].

Associations of PTH with chemical compounds

• We conclude that PTH and PLP activate adenylate cyclase by binding to common receptors in bone and kidney [27].
• Desensitization by hPTH did not affect responses to either InsP3 or serotonin, but cells desensitized to injected InsP3 still responded strongly to PTH [28].
• Oocytes did not respond to either cADPR or NAADP+, but NADP+ and analogues were found to be potent inhibitors of PTH signaling [28].
• Interestingly, OA osteoblasts produced more prostaglandin E2 (PGE2) than normal osteoblasts, and using naproxen, a cyclo-oxygenase inhibitor, increased PTH-dependent cAMP formation to a level similar to normal osteoblasts [29].
• Despite the reduction of plasma Ca(2+), no stimulation of PTH 1-84 secretion took place [4].

Physical interactions of PTH

• Likewise, PLP peptides and bPTH-(1-34) were equipotent in competing with 125I-bPTH-(1-34) for binding to PTH receptors in renal membranes [27].
• Synthetic hPTH (1-84) was found to be highly potent in binding to PTH receptors (Kb = 1-25 nM) and stimulating adenylate cyclase (Km = 1-14 nM) [30].
• PTH-stimulated cyclic adenosine monophosphate (cAMP) generation was determined by radioimmunoassay (RIA), PTH binding and PTH1R mRNA levels were determined by radioligand binding and Northern analysis, respectively [31].
• G alpha q family members couple parathyroid hormone (PTH)/PTH-related peptide and calcitonin receptors to phospholipase C in COS-7 cells [32].
• The receptor for parathyroid hormone and parathyroid hormone-related peptide is hydrolyzed and its signaling properties are altered by directly binding the calpain small subunit [33].
• We conclude that whereas PTH and PTHrP bind similarly to the G protein-coupled PTHR conformation (RG), PTH has a greater capacity to bind to the G protein-uncoupled conformation (R(0)) and, hence, can produce cumulatively greater signaling responses (via R(0)-->RG isomerization) than can PTHrP [34].

Enzymatic interactions of PTH

• We also showed that a synthetic peptide comprising the -6 to +7 sequence of human pro-PTH is appropriately cleaved by purified furin in vitro [35].
• When serine residues at positions 483, 485, 486, 489, 495, and 498 were simultaneously replaced by alanine residues, the PTH receptor was no longer phosphorylated either basally or in response to PTH [36].
• CONCLUSION: These data suggest that NaPi-IIa and PTH-induced phosphorylated proteins that include ezrin are compartmentalized in LDM microdomains [37].
• METHODS: We examined the submembrane localization of NaPi-IIa in opossum kidney (OK-N2) cells that stably expressed human NaPi-IIa, and searched for a PTH-induced specific phosphorylating substrate on their membrane microdomains by immunoblotting with specific antibody against phospho substrates of protein kinases [37].

Co-localisations of PTH

• Immunoelectron microscopical examination demonstrated that PTHrP co-localized with PTH in the same secretory granules [3].
• CYP2D6 was colocalized with parathyroid hormone in parathyroid chief cells [38].

Regulatory relationships of PTH

• However, PTH stimulated trafficking of these molecules for a chimeric PTH2R containing the N terminus and third extracellular loop of PTH receptor type 1 (PTH1R) [39].
• In vivo demonstration that human parathyroid hormone 1-38 inhibits the expression of osteoprotegerin in bone with the kinetics of an immediate early gene [40].
• These results suggest that both IGF-1 signaling and PGE2 formation repress PTH-dependent response in OA osteoblasts, a situation that can contribute to abnormal bone remodeling and bone sclerosis in OA [29].
• The (3-34) PTH antagonist inhibited the hPTHrP-induced vasodilatation [41].
• The inhibitory effect of 1alpha,25(OH)(2)D(3) on the PTH-induced expression of RANKL mRNA occurred only with physiological doses of the vitamin [42].

Other interactions of PTH

• The results demonstrate that (a) either the intact PTH molecule or a C-terminal fragment(s) bigger than 53-84 moiety exerts the inhibitory effect on erythropoiesis, and (b) adequate amounts of Ep can overcome this action of PTH [1].
• Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism [43].
• Menin inactivation leads to loss of transforming growth factor beta inhibition of parathyroid cell proliferation and parathyroid hormone secretion [25].
• Identification and functional expression of a receptor selectively recognizing parathyroid hormone, the PTH2 receptor [44].
• Impact of the mitogen-activated protein kinase pathway on parathyroid hormone-related protein actions in osteoblasts [45].

Analytical, diagnostic and therapeutic context of PTH

• We have investigated the contributions of PTHrP and parathyroid hormone (PTH) to the hypercalcaemia seen in routine clinical practice by means of highly sensitive immunoradiometric assays [46].
• PTH biosynthetic products in cell extracts and media were purified by high performance liquid chromatography, identified by radioimmunoassay, and unambiguously defined as either proPTH or PTH by ion-spray mass spectrometry [47].
• Each justifies special and similar approaches to parathyroidectomy: typically, identification of four glands, subtotal parathyroidectomy, rapid intraoperative parathyroid hormone (PTH) assays, and parathyroid cryopreservation [48].
• To determine whether PTHrP also potentially could have direct effects on antler osteoclasts, we studied, by confocal microscopy, the expression of the type I PTH/PTHrP receptor (PTH1R) in MNCs cultured on glass and found the receptor protein to have a nuclear localization [49].
• Furthermore, the mean age at onset of symptoms, body mass index, frequency of cataract, tetany, convulsion, basal ganglia calcification, serum calcium, inorganic phosphorus, and intact PTH were not significantly different between patients with and without the above-described SNPs [50].

References