Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0221002 (primary hyperparathyroidism)
 4,921 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By interacting with a structurally identical receptor, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) display a common spectrum of action on the transport of mineral elements in bone and kidney. In vivo, PTH/PTHrP similarly reduce the renal tubular reabsorption of inorganic phosphate (Pi) and increase that of calcium. The hypercalcemic effect of PTHrP is due to an increase in both bone resorption and renal calcium reabsorption, the latter through a sodium-independent mechanism. The PTHrP-stimulated bone resorption can be totally inhibited by bisphosphonate therapy. Despite that, the fall in calcemia is moderate, indicating that the PTHrP main hypercalcemic action is due to the stimulation of the renal transport of calcium. For identical effects on renal ionic transports, PTHrP appears to less stimulate bone formation than PTH. These experimental findings are similar to clinical observations in patients with primary hyperparathyroidism or with solid malignant tumors. In vitro, the effects of PTH(1-34), PTHrP(1-34) and PTHrP(1-141) on cAMP production and sodium-dependent phosphate transport (NaPiT) are similar in kidney cells, where NaPiT is specifically inhibited by either peptide. This effect is attenuated by the competitive inhibitor [D-Trp12,Tyr34]bPTH(7-34)amide. Transforming growth factor-alpha similarly modulates the cAMP and NaPiT responses to PTH/PTHrP. In cultured mammary cells isolated from lactating rats, PTHrP elicits a 2-fold increase of cAMP production. Various products of bone and stromal cells, and of leukocytes, such as Interleukin-6 or Tumor necrosis factor-alpha, as well as high extracellular calcium concentration enhance PTHrP production by cultured lung squamous cell carcinoma and Leydig tumor cells, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Actions of parathyroid hormone and parathyroid hormone-related protein. 133 36

The pathogenesis of PTH-induced bone loss is uncertain. Experimental evidence suggests that PTH induces the production by osteoblasts of the bone-resorbing cytokine, interleukin-6. We measured the circulating levels of interleukin-6, tumor necrosis factor-alpha, and interleukin-1 beta and examined their relationship to biochemical markers of bone turnover in 38 patients with primary hyperparathyroidism (7 of whom also were studied after successful parathyroid adenomectomy), 6 patients with hypoparathyroidism, and 12 subjects with normal parathyroid function. The patients with untreated primary hyperparathyroidism had mean serum levels of interleukin-6 that were 16-fold higher than control values (mean +/- SEM; primary hyperparathyroidism 18.6 +/- 2.1 pg/mL, controls 1.1 +/- 0.1; P < 0.001). Circulating levels of interleukin-6 soluble receptor (primary hyperparathyroidism 41.7 +/- 1.2 ng/ mL, controls 25.1 +/- 1.0; P < 0.001), and tumor necrosis factor-alpha (primary hyperparathyroidism 11.6 +/- 0.8 pg/mL, controls 2.5 +/- 0.2; P < 0.001) were also elevated. After successful parathyroid adenomectomy, levels of each of these cytokines fell into the normal range. The mean levels of interleukin-6, its soluble receptor, and tumor necrosis factor-alpha in the subjects with hypoparathyroidism were lower than control values (P < 0.001 for each variable). There was no difference between subjects with primary hyperparathyroidism and controls in the circulating level of interleukin-1 beta. In the subjects with untreated primary hyperparathyroidism, serum levels of interleukin-6 correlated strongly with those of intact PTH (r = 0.47, P = 0.003) and biochemical markers of bone resorption: serum deoxypyridinoline (r = 0.93, P < 0.001), serum type I collagen carboxyterminal telopeptide (r = 0.87, P < 0.001), urinary pyridinoline (r = 0.81, P < 0.001), and urinary deoxypyridinoline (r = 0.63, P = 0.005). Levels of tumor necrosis factor-alpha correlated less strongly with the same variables: PTH (r = 0.41, P = 0.01), serum deoxypyridinoline (r = 0.48, P = 0.002), serum type I collagen carboxyterminal telopeptide (r = 0.46, P = 0.004), urinary pyridinoline (r = 0.61, P = 0.008), and urinary deoxypyridinoline (r = 0.61, P = 0.007). Levels of interleukin-6 also correlated with those of tumor necrosis factor-alpha (r = 0.44, P = 0.005). Multiple regression analysis indicated that interleukin-6, but not tumor necrosis factor-alpha, was independently predictive of bone resorption. We conclude that serum levels of interleukin-6 and tumor necrosis factor-alpha are increased in patients with primary hyperparathyroidism and are normalized by successful surgical treatment. The finding that these cytokines correlate with biochemical markers of bone resorption suggests that they play a role in the pathogenesis of bone loss in primary hyperparathyroidism.
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PMID:Circulating levels of interleukin-6 and tumor necrosis factor-alpha are elevated in primary hyperparathyroidism and correlate with markers of bone resorption--a clinical research center study. 885 82

Parathyroid hormone (PTH) exerts its regulatory effects on calcium homeostasis in part by stimulating the release of calcium from the skeleton. PTH stimulates bone resorption indirectly, by inducing the production by stromal/osteoblastic cells of paracrine agents which recruit and activate the bone-resorbing cell, the osteoclast. The identity of the stromal cell/osteoblast-derived paracrine factor(s) responsible for mediating the effects of PTH on osteoclasts is uncertain. Recently, it has been demonstrated that the cytokine interleukin-6 (IL-6), which potently induces osteoclastogenesis, is produced by osteoblastic cells in response to PTH. Further, we have reported that circulating levels of IL-6 are elevated in patients with primary hyperparathyroidism, and correlate with biochemical markers of bone resorption. Thus, IL-6 may play a permissive role in PTH-induced bone resorption. In the current studies, we demonstrate that low-dose PTH infusion in rodents increased serum levels of IL-6, coincident with a rise in biochemical markers of bone resorption. In mice, both acute neutralization and chronic deficiency of IL-6 were associated with markedly lower levels of biochemical markers of bone resorption in response to PTH infusion than were observed in animals with normal IL-6 production. Acute neutralization of IL-6 did not affect PTH-induced changes in markers of bone formation. These findings demonstrate that PTH regulates systemic levels of IL-6 in experimental animals, that IL-6 is an important mediator of the bone-resorbing actions of PTH in vivo and suggest that IL-6 plays a role in coupling PTH-induced bone resorption and formation.
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PMID:A role for interleukin-6 in parathyroid hormone-induced bone resorption in vivo. 1049 26

We have observed a strong correlation between circulating levels of both interleukin-6 (IL-6) and interleukin-6 soluble receptor (IL-6sR) and rates of bone turnover in patients with primary hyperparathyroidism. Furthermore, we have found that serum levels of IL-6sR predict rates of bone loss in postmenopausal women with this disease. Estrogen modulates parathyroid hormone (PTH)-induced increases in serum IL-6/IL-6sR, such that, in the estrogen-deficient state, there is an exaggerated release of these cytokines. We therefore propose that the perimenopausal period represents a time when skeletal sensitivity to the resorbing actions of PTH increases because of augmented release of IL-6 and IL-6sR. To test this hypothesis, we retrospectively examined data from 91 women with primary hyperparathyroidism who were seen over the last 5 years at our institution. Women were categorized, based on their age, as premenopausal (n = 20, 41 +/- 2 years), perimenopausal (n = 17, 54 +/- 1 years), or postmenopausal (n = 54, 64 +/- 1 years). Despite having similar mean values for PTH, perimenopausal women had a mean serum IL-6 value that was significantly higher than that in the premenopausal group (13 +/- 2 vs. 8 +/- 2 pg/ml; p = 0.03). This difference in cytokine profile was mirrored by higher mean values for urine N telopeptides of type I collagen (NTX) in the perimenopausal group compared with premenopausal women (114 +/- 9 vs. 80 +/- 11 nM bone collagen equivalents (BCE)/mM creatinine, p = 0.01). Of the three groups of patients, values for IL-6 and urine NTX were highest in the postmenopausal group. We conclude that the perimenopausal period may be a time of increased risk for the skeletal complications of hyperparathyroidism. This is because of increased skeletal sensitivity to the resorbing actions of PTH, mediated in part, by the IL-6/IL-6sR cytokine system.
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PMID:Role of the interleukin-6/interleukin-6 soluble receptor cytokine system in mediating increased skeletal sensitivity to parathyroid hormone in perimenopausal women. 1241 87

Parathyroid hormone (PTH) stimulates osteoblasts to produce the proinflammatory cytokine interleukin-6 (IL-6), causing bone resorption. In patients with primary hyperparathyroidism, elevated serum levels of IL-6 normalize after resection of parathyroid tumours. Because IL-6 is also expressed in normal parathyroids and in other endocrine cells (adrenal and islet), we hypothesized that parathyroid tumours might contribute directly to the elevated serum IL-6 levels in patients with hyperparathyroidism. Immunohistochemistry identified IL-6, PTH, and chromogranin-A (an endocrine and neuroendocrine tumour marker) in normal, adenomatous and hyperplastic parathyroids. Using immunofluorescence and confocal microscopy, IL-6 co-localized with PTH and with chromogranin-A in parathyroid cells. All cultured parathyroid tumours secreted IL-6 at levels markedly higher than optimally stimulated peripheral blood mononuclear cells. Supernates from cultured parathyroids stimulated proliferation of an IL-6-dependent cell line, and anti-IL-6 MoAb abolished this stimulatory effect. IL-6 mRNA was documented in cultured parathyroid tumours, cultured normal parathyroids, fresh operative parathyroid tumours and fresh operative normal specimens. In conclusion, these data show that parathyroid tumours and normal parathyroids contain, produce and secrete IL-6. Our findings present a novel pathway by which human parathyroids may contribute markedly to IL-6 production and elevation of serum IL-6 levels in patients with hyperparathyroidism. The physiological relevance of IL-6 production by human parathyroids remains to be determined, but IL-6 secretion by parathyroid tumours may contribute to bone loss and to other multi-system complaints observed in these patients.
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PMID:Interleukin-6 production and secretion by human parathyroids. 1503 May 26