Anabolic action of parathyroid hormone regulated by the β2-adrenergic receptor

Parathyroid hormone (PTH), the major calcium-regulating hormone, and norepinephrine (NE), the principal neurotransmitter of sympathetic nerves, regulate bone remodeling by activating distinct cell-surface G protein-coupled receptors in osteoblasts: the parathyroid hormone type 1 receptor (PTHR) and the β(2)-adrenergic receptor (β(2)AR), respectively. These receptors activate a common cAMP/PKA signal transduction pathway mediated through the stimulatory heterotrimeric G protein. Activation of β(2)AR via the sympathetic nervous system decreases bone formation and increases bone resorption. Conversely, daily injection of PTH (1-34), a regimen known as intermittent (i)PTH treatment, increases bone mass through the stimulation of trabecular and cortical bone formation and decreases fracture incidences in severe cases of osteoporosis. Here, we show that iPTH has no osteoanabolic activity in mice lacking the β(2)AR. β(2)AR deficiency suppressed both iPTH-induced increase in bone formation and resorption. We showed that the lack of β(2)AR blocks expression of iPTH-target genes involved in bone formation and resorption that are regulated by the cAMP/PKA pathway. These data implicate an unexpected functional interaction between PTHR and β(2)AR, two G protein-coupled receptors from distinct families, which control bone formation and PTH anabolism.     

Is the treatment of Hodgkin's disease detrimental to the parathyroid gland?

The thyroid gland is often injured by supradiaphragmatic irradiation for Hodgkin's lymphoma. The aim of the present study was to examine whether the parathyroid gland gets injured by the treatment for Hodgkin's disease. Calcium, phosphorus and parathormone levels of 143 patients with primary treatment for Hodgkin's disease and in complete remission for 2 years were measured as well as the presence of antiparathyroid antibody in patients having antithyroid antibody. Out of the 143 patients studied, 104 received neck irradiation (with or without chemotherapy); among them laboratory alterations were observed in 7 cases. 39 patients received only chemotherapy; 3 of them had alterations. In contrast to the injury of the thyroid gland, no damage to the parathyroid glands associated with the treatment for Hodgkin's disease was noted. It has been concluded that the use of high-dose external radiotherapy does not mean a higher risk as regards the parathyroid gland but further follow-up studies of the patients may result in the revelation of the development of parathyroid lesions.     

Referral of patients with parathyroid dysfunction to specialists--which patients should be referred to parathyroidologists?

Although a diagnosis of primary hyperparathyroidism and hypothyroidism becomes very easy at the present time due to development of highly sensitive assay for parathyroid hormone, the diagnosis of hyper- and hypothyroidism should be made by excluding the loss and gain of function mutation of calcium sensing receptor, respectively. When a diagnosis of primary hyperparathyroidism is made but the localization of adenoma(s) is not identified, the patient should be referred to specialists for parathyroid surgery. Although patients with primary hypoparathyroidism can be followed by a general physician, they should be referred to specialists when they become pregnant, since active vitamin D is increased and decreased in the late pregnancy and in the postpartum period, respectively.     

Full length parathyroid hormone (1–84) in the treatment of osteoporosis in postmenopausal women

Objective:

To review the pharmacological properties and the available clinical data of full length parathyroid hormone (PTH) in post-menopausal osteoporosis.

Sources:

A MEDLINE search was completed, together with a review of information obtained from the manufacturer and from the medicine regulatory agencies.

Study and data selection:

Studies were selected according to relevance and availability. Relevant information (design, objectives, patients’ characteristics, outcomes, adverse events, dosing, etc) was analyzed.

Results:

Different studies have shown that, when administered intermittently as a subcutaneous injection in the abdomen, PTH increases bone mineral density (BMD) and prevents vertebral fractures. On completion of PTH therapy (up to 24 months), there is evidence that sequential treatment with alendronate is associated with a therapeutic benefit in terms of increase in BMD. Further trials are necessary to determine long-term safety and the role of PTH in combination with other treatments for osteoporosis and the effect of repeated cycles of PTH followed by an anti-catabolic agent. There are currently no completed comparative trials with other osteoporosis treatments.

Conclusions:

Full length PTH, given intermittently as an abdominal subcutaneous injection, appears to be a safe and efficacious treatment option for high risk osteoporosis. More data are needed to determine its specific role in osteoporosis treatment.     

Disturbances of parathyroid hormone–vitamin D axis in non-cholestatic chronic liver disease: a cross-sectional study

Purpose  

Liver has an important role in metabolism of vitamin D. This study aimed to evaluate the patterns of vitamin D–parathyroid hormone (PTH) disturbance and correlate it in patients with non-cholestatic chronic liver disease (CLD).     

How to localize parathyroid tumors in primary hyperparathyroidism?

The management of primary hyperparathyroidism (PHPT) has dramatically changed in the last 5 yr. Many more patients now undergo focused, limited or minimally invasive parathyroidectomy instead of traditional bilateral neck exploration. This change has taken place because of the improved accuracy of pre-operative localizing studies in selecting patients who have single-gland parathyroid disease (single adenoma) and can therefore have a minimally invasive parathyroidectomy. Sestamibi scanning followed by ultrasound, magnetic resonance imaging (MRI) and computed tomography (CT) scans are most accurate for localizing parathyroid tumors in patients with PHPT. Selective venous catheterization for PTH levels is useful when other localizing studies are negative or discordant in patients with persistent or recurrent PHPT. The routine use of one or more localizing studies commonly identifies the parathyroid tumor in patients with single-gland disease; but if localizing studies are negative or discordant, patients should have intra-operative PTH levels monitored or have a bilateral neck exploration to ensure a high rate of biochemical cure.     

Experimental parathyroid hormone gene therapy using ØC31 integrase

?C31 integrase can integrate targeted plasmid DNA into preferred locations in mammalian genomes, resulting in robust, long-term expression of the integrated transgene. This system represents an effective tool that opens up promising possibilities for gene therapy. The classical treatment for hypoparathyroidism was calcium and vitamin D replacement. Recently, parathyroid hormone (PTH) replacement was reported to be a more potentially physiologic treatment option. However, PTH synthesis is technically difficult and costly. These issues may be minimized by using PTH gene therapy. We attempted to achieve site-specific genomic integration of the PTH gene into a human cell line and mice using this system. We cotransfected 293 HEK cells with PTH-attB plasmid with or without ?C31 integrase plasmid. Expression and secretion of PTH into culture supernatants and site-specific genomic integration of PTH cDNA were assessed by immunoradiometric assays and pseudo-site analysis, respectively. In in vivo experiments, we injected the PTH-attB plasmid with or without ?C31 integrase plasmid into a mouse tail vein using the hydrodynamic method. Plasma PTH concentrations were serially measured, and site-specific integration of PTH cDNA into the mouse genome was confirmed by examining hepatic genomic DNA. PTH was expressed and secreted from 293 HEK cells and mouse hepatocytes, and pseudo-site analysis confirmed the site-specific integration of PTH cDNA into the host genomes. The site-specificity and efficiency of this system are advantageous in many areas, including, potentially, gene therapy. PTH gene therapy is one candidate; however, for clinical applications, we need to regulate PTH expression and secretion in the future.     

Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma?

OBJECTIVE: HRPT2 gene mutations are associated with parathyroid carcinomas, and absence of parafibromin immunoreactivity has been suggested as a diagnostic marker of malignancy. The aim of our study was to extend parafibromin studies in a series of benign and malignant parathyroid tumors and cross-validate the results of immunohistochemistry with those of HRPT2 analysis. DESIGN AND PATIENTS: We performed parafibromin and cyclin D1 immunostaining and HRPT2 gene analysis using loss of heterozygosity studies and sequencing analysis in parathyroid specimens from 11 patients with carcinoma (eleven primary tumors, one skin, and four lung metastases), 22 with sporadic adenomas, and 4 with atypical adenomas. RESULTS: Ten out of eleven parathyroid cancers were negative for parafibromin staining and showed HRPT2 gene abnormalities. The remaining sample was negative for immunostaining and genetic analyses. All but one sporadic adenomas showed parafibromin immunoreactivity and no HRPT2 gene abnormalities. The sample with negative immunostaining carried an HRPT2 mutation. Two atypical adenomas were positive and two negative with parafibromin staining. No HRPT2 abnormalities were found in these samples. Cyclin D1 expression was heterogeneous and there was no relationship between expression/expression level of cyclin D1 and parafibromin expression. CONCLUSIONS: We have shown that negative parafibromin staining is almost invariably associated with HRPT2 mutations and confirm that loss of parafibromin staining strongly predicts parathyroid malignancy. In clinical practice, these tests could be particularly useful in the subset of parathyroid tumors with equivocal histological examination. However, their diagnostic value in this setting remains to be proven.     

Familial parathyroid hyperplasia: is there a place for minimally invasive surgery? Description of the first treated case

While the majority of patients affected with sporadic primary hyperparathyroidism (sPHPT) can be selected for minimal access surgery, patients affected with 4-gland hyperplasia still do not represent an indication for it. Minimally invasive video-assisted parathyroidectomy (MIVAP) was introduced in 1996; this technique relies on a single central incision and external retraction and therefore allows a bilateral neck exploration. This was the case of a 27-yr-old female with familial primary hyperparathyroidism (FPHPT). Three enlarged glands were immediately identified in orthotopic positions and the fourth was intrathyroideal. A subtotal parathyroidectomy was then performed, leaving a small fragment of the inferior right gland and completed with the cervical thymectomy by inverting the positions of the camera and the retractor assistants with regard to the positions originally described. Quick intraoperative PTH assay (QPTH) confirmed the surgical cure of the disease.     

Can parathyroid hormone be used as a biomarker for heart failure?

Secondary hyperparathyroidism in heart failure is a consequence of renin–angiotensin–aldosterone activation, chronic hyperaldosteronism, and loop diuretic usage, resulting in calcium excretion. The result is an inflammatory state with adverse effects on myocardial remodeling and systemic complications. Recent literature has suggested that elevated parathyroid hormone predicts adverse outcomes in patients with heart failure independent of serum calcium and phosphate, vitamin D deficiency, and renal insufficiency. Parathyroid hormone has been correlated with elevated brain natriuretic peptide levels, an established biomarker of heart failure severity. There are several limitations to the utilization of parathyroid hormone as a biomarker for heart failure, and further prospective studies need to be conducted to assess the value of multiple parathyroid hormone measurements over time and elucidate the role of parathyroid hormone in diastolic dysfunction. Pending further validation, there is promise for parathyroid hormone as a complementary biomarker in heart failure.     

Elevated parathyroid hormone 44-68 in idiopathic calcium pyrophosphate dihydrate crystal deposition disease. Role of menopause and iron metabolism?

OBJECTIVE: To examine whether idiopathic calcium pyrophosphate dihydrate (CPPD) crystal deposition disease (CDD) is related to altered parathyroid hormone (PTH) metabolism. METHODS: Forty-two patients with idiopathic CPPD CDD were compared with 67 controls, 33 of whom were matched for age and sex. RESULTS: Serum PTH 44-68 concentrations were elevated in 29% of patients and were significantly higher in the patients than in their sex- and age-matched controls (Z = -4.664, p < 0.0001). PTH 1-84 levels were normal. Serum calcium, phosphorus, and ferritin levels were normal, but were significantly higher in the patients. Serum PTH 44-68 levels correlated negatively with serum transferrin in female controls aged >or= 45 years, and with transferrin saturation in the female patients. Correlation between serum ferritin and age was linear and positive in the former subjects and quadratic in the latter. CONCLUSION: Elevated serum concentration of PTH mid-fragments containing the 44-68 region could explain the joint disorders associated with idiopathic CPPD CDD, as shown in genetic hemochromatosis. In female patients the elevation of PTH mid-fragments could be linked to changes in iron metabolism provoked by the menopause.     

The expression of p27~(Kip1) and β-catenin in multiple endocrine neoplasia type 1-related parathyroid tumors

正Objective To explore tissue expression of cyclin-dependent kinase inhibitor p27~(Kip1) andβ-catenin in multiple endocrine neoplasia type1(MEN1)-related parathyroid tumors(MHPT).Methods Immunohistochemistry was performed to analyze the expression of p27~(Kip1) andβ-catenin in parathyroid glands from 31 subjects with     

Expression and biological activity of parathyroid hormone-related peptide in pregnant rat uterine artery: any role for 8-iso-prostaglandin F2alpha?

PTHrP is produced in vessels and acts as a local modulator of tone. We recently reported that PTHrP(1-34) is able to induce vasorelaxation in rat uterine arteries, but in pregnancy, this response is blunted and becomes strictly endothelium dependent. The present study aimed to get insights into the mechanisms involved in these changes because the adaptation of uterine blood flow is essential for fetal development. On d 20 of gestation, RT-PCR analysis of uterine arteries showed that PTH/PTHrP receptor (PTH1R) mRNA expression was decreased, whereas that of PTHrP mRNA was increased. This was associated with a redistribution of the PTHrP/PTH1R system, with both PTH1R protein and PTHrP peptide becoming concentrated in the intimal layer of arteries from pregnant rats. On the other hand, the blunted vasorelaxation induced by PTHrP(1-34) in uterine arteries from pregnant rats was specifically restored by indomethacin and a specific cyclooxygenase-2 inhibitor, NS 398. This was associated with an increase in cyclooxygenase-2 expression and in 8-iso-prostaglandin F(2alpha) release when uterine arteries from pregnant rats were exposed to high levels of PTHrP(1-34). Most interestingly, 8-iso-prostaglandin F(2alpha) itself was able to increase PTHrP expression and reduce PTH1R expression in cultured rat aortic smooth muscle cells. These results suggest a local regulation of uterine artery functions by PTHrP during pregnancy resulting from PTH1R redistribution. Moreover, they shed light on a potential role of 8-iso-prostaglandin F(2alpha).