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PubMed2006

Skeletal metastasis: Established and emerging roles of parathyroid hormone related protein (PTHrP).

Parathyroid hormone related protein (PTHrP) is a well characterized tumor derived product that also has integral functions in normal development and homeostasis. PTHrP is produced by virtually all tumor types that metastasize to bone and numerous studies have demonstrated a correlation between PTHrP expression and skeletal localization of tumors. PTHrP has prominent effects in bone via its interaction with the PTH-1 receptor on osteoblastic cells. Through indirect means, PTHrP supports osteoclastogenesis by upregulating the receptor activator of NFkappaB ligand (RANKL) in osteoblasts. PTHrP also regulates osteoblast proliferation and differentiation in manners that are temporal and dose dependent. Bone turnover has been implicated in the localization of tumors to bone and PTHrP increases bone turnover. Bone turnover results in the release of growth factors such as TGFbeta and minerals such as calcium, both of which impact tumor cell growth and contribute to continued PTHrP production. PTHrP also has anabolic properties and could be in part responsible for osteoblastic type reactions in prostate cancer. Finally, emerging roles of PTH and PTHrP in the support of hematopoietic stem cell development in the bone marrow microenvironment suggest that an interaction between hematopoietic cells and tumor cells warrants further investigation.

Animals↗
PubMed1997

A prospective study of calciotropic hormones in pregnancy and post partum: reciprocal changes in serum intact parathyroid hormone and 1,25-dihydroxyvitamin D.

OBJECTIVE: The purpose of this study was to examine the hormones regulating calcium homeostasis longitudinally in pregnancy and post partum. STUDY DESIGN: Twenty-three women with normal pregnancies were studied in the second and third trimesters and post partum. At each time blood was analyzed for ionized calcium, vitamin D metabolites, and intact parathyroid hormone, and a 24-hour urine specimen was analyzed for creatinine, calcium, and sodium. RESULTS: Urinary calcium excretion was 250% to 300% higher during pregnancy than post partum (p < 0.00001). 1,25-Dihydroxyvitamin D levels were equivalent in the second and third trimesters but were twofold higher than postpartum values (p < 0.01). Ionized calcium was similar at all time points. Intact parathyroid hormone in the second and third trimesters was 50% of postpartum levels (p < 0.001). CONCLUSION: Pregnancy is associated with an increase in the levels of 1,25-dihydroxyvitamin D and a concomitant reciprocal fall in intact parathyroid hormone levels. The increase in serum 1,25-dihydroxyvitamin D values appears to be a key factor in providing for the increase in maternal calcium requirements during pregnancy.

Adult↗
PubMed2005

[A study on polymerase chain reaction site-directed mutagenesis of prepro-parathyroid hormone in vitro].

OBJECTIVE: To study PCR site-directed mutagenesis of prepro-parathyroid hormone gene in vitro and let furin convert it into mature parathyroid hormone in human cells. METHOD: Prepro-parathyroid hormone cDNA of SD rat was cloned from its genomic gene and mutated by overlap mutant PCR, introducing furin consensus sequences (Arg-Lys-Lys-Arg). An expression pcDNA3.1/mPTH vector encoding a genetically modified prepro-parathyroid hormone cDNA was generated, and transduced to 293 cells by lipofectin-mediated DNA transfection. Forty-eight and 72 h after the transfection, the culture media were collected for further assay with radioimmunoassay. RESULTS: A fragment of prepro-parathyroid hormone gene was cloned and one site were mutated simultaneouly. After screening and sequencing of pcDNA3.1/mPTH vectors, a correctly mutated vectors was obtained. While measuring parathyroid hormone in the medium of the expressing 293 cells by RIA method, the results of transient expression were 28.34 - 52.64 pg/2.0 x 10(6)/cells/Day, which were much higher than that in control cells. CONCLUSIONS: A correctly mutated prepro-parathyroid hormone cDNA was obtained successfully, transfected, and expressed efficiently in human cells.

Animals↗
PubMed1985

Increased cyclic AMP in cultured vascular smooth muscle cells and relaxation of aortic strips by parathyroid hormone.

The effects of parathyroid hormone (PTH) were examined in three model systems to determine the mechanism of PTH action in vascular tissue. Bovine parathyroid extract and synthetic bPTH-(1-34) relaxed norepinephrine-contracted rabbit aortic strips in a dose-dependent fashion. The ED50 was 33.1 nM (21.8-50.1 nM). The hypotensive diterpene, forskolin and the phosphodiesterase inhibitors, methylisobutylxanthine and papaverine, all greatly potentiated the relaxant action of PTH. Primary cultures of vascular smooth muscle cells isolated from rabbit and rat aorta and bovine pulmonary artery all responded to bPTH-(1-34) with 5- to 10-fold increases in intracellular cyclic AMP concentrations within 1 min. Again, this action of PTH was also markedly augmented (3-fold or greater) by methylisobutylxanthine, papaverine or forskolin. In addition, 1 microM bPTH-(1-34) stimulated adenylate cyclase activity in membrane preparations from vascular smooth muscle cells in the presence or absence of 100 microM GMPPNHP. These results indicate that PTH exerts direct relaxant actions on vascular smooth muscle and that cyclic AMP may be involved in the mechanism of PTH action in vascular tissue.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Regulation of parathyroid hormone gene expression and peptide secretion in human parathyroid cells.

In cell cultures prepared from human parathyroid adenomas, parathyroid hormone (PTH) mRNA expression decreased slowly. During short-term incubations (less than 24 h), a low calcium concentration (0.5 mmol/l) and protein kinase C activator TPA (12-O-tetradecanoyl phorbol 13-acetate) (160 nmol/l) increased PTH secretion (60%; p < 0.05), while a high extracellular calcium concentration (2.5 mmol/l) reduced PTH secretion (60%; p < 0.05). The TPA could block the inhibitory effect of a high calcium level on PTH peptide secretion. All these agents had no effect on PTH mRNA accumulation in short-term experiments. In long-term cultures (more than 24 h), a low calcium level increased and a high calcium level reduced both PTH mRNA (85 and 34%; p < 0.05) and peptide secretion (140 and 80%; p < 0.05), respectively. The TPA reduced PTH mRNA accumulation down to 30% (p < 0.05) and PTH secretion down to 14% (p < 0.05) in a time- and dose-dependent fashion. The TPA also reversed the stimulatory effect of hypocalcemia on PTH mRNA accumulation and peptide secretion. Protein kinase C inhibitors staurosporine (100 nmol/l) and H-7 (1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride) (50 mumol/l) had similar effects to TPA on PTH gene expression and peptide secretion in long-term cultures. The results support the hypothesis that extracellular calcium regulates PTH mRNA accumulation and PTH secretion via protein kinase C.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1978

Autoantibodies to parathyroid hormone receptor.

Autoantibodies which block the binding of parathyroid hormone to membrane receptors for the hormone were detected in the sera (especially in the IgG fraction) of 49 out of 50 uraemic patients with secondary hyperparathyroidism (patients with high levels of C-regional parathyroid hormone). These antibodies are species-specific. Their presence in the serum in unaffected by dialysis. Inhibition of binding appears to be related to the rise in C-regional parathyroid-hormone levels and the duration of uraemia. The production of cyclic adenosine monophosphate by parathyroid-hormone-stimulated adenyl cyclase was reduced by the blocking antibodies. The findings show that secondary hyperparathyrodism in uraemia is another example of a receptor-antibody disease, but it is not known whether the antibodies act by modifying the affinity of the receptors for the hormone or by reducing the concentration of receptors available.

Animals↗
PubMed1977

Immunoheterogeneity of parathyroid hormone in venous effluent serum from hyperfunctioning parathyroid glands.

The immunoreactive parathyroid hormone (iPTH) in the plasma of hyperparathyroid man consists largely of carboxyl (COOH)-terminal fragments of the hormone. Although these fragments have been thought to arise principally or solely from peripheral metabolism of intact human PTH {hPTH(1-84)} secreted from the parathyroid gland, there is disagreement about the source of iPTH fragments in vivo. To reexamine this question, we fractionated peripheral and thyroid or parathyroid venous effluent sera from four patients with primary hyperparathyroidism using a high-resolution gel filtration system (Bio-Gel P-150 columns run by reverse flow). The column effluents were analyzed using two PTH radioimmunoassays, one directed toward the amino(NH(2))-terminal region of the molecule, the other toward the COOH-terminal region. In all four thyroid or parathyroid venous effluent sera studied, iPTH was 9-180 times higher than in peripheral serum from the same patient; after fractionation, hPTH(1-84) accounted for only a portion of the total iPTH (35-55% with the assay directed toward the COOH-terminal region of hPTH, >90% with the NH(2)-terminal directed assay.) The remaining iPTH eluted from Bio-Gel P-150 after hPTH(1-84) as NH(2)-or COOH-terminal hPTH fragments. These results suggest that parathyroid tumors secrete large quantities of hPTH fragments. Based on estimates of their molar concentrations in serum, tumor-secreted COOH-terminal hPTH fragments could account for most of these peptides in peripheral serum if their survival times were, as estimated by several other workers, 5-10 times that of hPTH(1-84). We conclude that, in contrast to published information, secretory products of hyperfunctioning parathyroid tissue are probably a major source of serum PTH immunoheterogeneity.

Adult↗
PubMed1976

Effect of parathyroid hormone on phosphate reabsorption in the presence of acetazolamide.

The hypothesis that parathyroid hormone and carbonic anhydrase inhibitors have a common mechanism or site of action on phosphate reabsorption by the renal tubule was tested by administration of parathyroid hormone in the absence and presence of acetazolamide in thyroparathyroidectomized dogs. Re-collection micropuncture and electron probe microanalysis methodologies were utilized. In the absence of acetazolamide, parathyroid hormone increased fractional delivery of phosphate (and volume) from the proximal tubule from 25 +/- 2 to 38 +/- 3%, P less than 0.025, and increased fractional phosphate excretion from 3.8 +/- 1.2 to 19.9 +/- 3.7%, P less than 0.005 (eight dogs). In the presence of acetazolamide, parathyroid hormone increased fractional delivery of phosphate (but not volume) from the proximal tubule from 50 +/- 4 to 58 +/- 5%, P less than 0.025, and increased fractional excretion of phosphate from 8.7 +/- 2.2 to 31.0 +/- 4.3%, P less than 0.001 (12 dogs). Thus, the effects of parathyroid hormone were additive to the effects of maximal inhibition of carbonic anhydrase indicating that parathyroid hormone and carbonic anhydrase inhibitors have different mechanisms of action on phosphate reabsorption by the renal tubule. In addition, phosphate reabsorption beyond the point of micropuncture in the late proximal tubule was much more markedly inhibited by parathyroid hormone than by acetazolamide.

Acetazolamide↗
PubMed1996

Hyaluronan synthesis by epiphysial chondrocytes is regulated by growth hormone, insulin-like growth factor-1, parathyroid hormone and transforming growth factor-beta 1.

In a previous study, we presented evidence that the synthesis of hyaluronan by hypertrophic chondrocytes is one of the principal factors driving the interstitial expansion of the growth plate (Pavasant et al., J. Cell Sci. 109: 327-334, 1996). To test this possibility further, we used two different approaches to examine the effects of hormones on the production of hyaluronan in the growth plate. In the first approach, we examined the growth plate of the lit/lit mouse that lacks growth hormone and found that its hypertrophic lacunae were smaller and contained less hyaluronan than those of wild type mice. Moreover, the ratios of hyaluronan staining density to total area of the lacunae were similar for the lit/lit and the wt/wt mice, indicating that the amount of hyaluronan is directly related to lacuna size. In the second approach, we examined the effects of hormones on segments of the epiphysial growth plate placed in organ culture. Under normal culture conditions, a band of hyaluronan staining progressed across the length of the growth plate, reflecting the maturation of chondrocytes into the hypertrophic stage. When insulin-like growth factor-1, a factor known to promote chondrocyte maturation, was added to the culture medium, the production of hyaluronan and the enlargement of the lacunae were stimulated. In contrast, when either parathyroid hormone or transforming growth factor-beta 1, both of which inhibit chondrocyte differentiation, was added to the medium of cultured segments, new pericellular hyaluronan was not detected and the lacunae did not enlarge. Taken together, these results indicate that factors that either stimulate or inhibit the maturation of epiphysial chondrocytes have a corresponding effect on the production of hyaluronan. This, in turn, further supports the importance of hyaluronan in the process of lacuna enlargement.

Animals↗
PubMed1994

Cyclic-AMP-dependent protein kinase activity is not required by parathyroid hormone to stimulate phosphoinositide signaling in chondrocytes but is required to transduce the hormone's proliferative effect.

Parathyroid hormone (PTH), an activator of both cAMP and phosphoinositide (PI) signaling in growth plate chondrocytes (GPCs), is generally believed to trigger each of these pathways through interactions with separate G proteins. Recently, however, activation of cAMP-dependent protein kinase (pkA) has been found to cause a stimulation of the PI cascade in hepatocytes. This finding raises the possibility that PTH stimulation of PI metabolism in GPCs may really be a secondary event, mediated through a primary stimulation of pkA. Experiments discussed in the present report indicate that the PTH stimulation of PI metabolism in GPCs is independent of pkA activity. The data show that (1) unlike the Ca2+ response evoked by PTH, the responses evoked by dibutyryl-cAMP or Sp diastereomer of cyclic adenosine-3',5'-monophosphothioate, two activators of pkA, require an extracellular Ca2+ source; (2) also unlike PTH, activation of pkA by these same cAMP analogs does not cause an increase in cellular inositol-1,4,5-trisphosphate; and (3) specific inhibition of pkA with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinsulfanomide (H-89) or Rp diastereomer of cyclic adenosine-3',5'-monophosphothioate (Rp cAMPS) has no effect on the ability of PTH to evoke its normal Ca2+ response. Furthermore, data presented indicate that the PTH stimulation of GPC proliferation does not require Ca2+ signals, but rather is at least partially dependent on pkA. The data show that either loading the cells with the Ca2+ buffer bis-(o-aminophenoxy)ethane-N,N,N',N'-tetracetic acid or depleting the cells of intracellularly stored Ca2+ is without effect on the stimulation of DNA synthesis by the hormone. Inhibition of pkA activity with H-89 or Rp-cAMPS, in contrast, leads to a significant reduction in the ability of PTH to stimulate its proliferative effect.

Animals↗