Failure of parathyroid hormone antagonists to inhibit in vitro bone resorbing activity produced by two animal models of the humoral hypercalcemia of malignancy.

D'Souza, S M; Ibbotson, K J; Mundy, Gregory R.

doi:10.1172/jci111478

Cited by 26 publications

(7 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PTH-Iike factors with molecular weights of 9,500 and 28,000 and in vivo calcium mobilising activity have been isolated from this model [11]. However, the osteoblastic cyclic AMP stimulating ability of Lcydig cell tumor medium is not inhibited by known IrI'H receptor antagonists, suggesting that a PTH-like factor is not the major bone resorbing factor in this model, or that its effects are not mediated through the PTH receptor [12]. Furthermore, there is the evidence that the responsible factor may display growth factor-as well as PTH-like activity and mediate its bone resorbing effects through interaction with the EGF receptor [13,14].…”

Section: Animal Modelsmentioning

confidence: 99%

“…The Walker 256 carcinosarcoma is a mammary tumour implantablc in rats that produces osteolysis and a humoral hypercalcaemic syndrome [16]. As with the Leydig cell tumor model, a PTH-like substance has been implicated in this model, but the adenylate cyclase stimulating effect of this material is not inhibited by PTH antagonists [12,17]. Inhibition of bone resorption with bisphosphonates does not correct the hypercalcaemia in thyroparathyroidectomised rats, bearing this tumour, suggesting that some humoral factor increases renal calcium reabsorption directly [18].…”

Section: Animal Modelsmentioning

confidence: 99%

“…It may display transforming growth factor-like activity ]141, or may act via EGF receptors [13]. Known PTH antagonists fail to prevent the stimulation of ostcoblastic cyclic AMP, a known PTH effect, by conditioned media from certain animal models associated with humoral hypercalcaemia of malignancy [12].…”

Section: Pth-related Peptidementioning

confidence: 99%

“…The ability of shorter PTHrP peptides to increase osteoblastic cyclic AMP activity has also been assessed [37]. PTHrP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and PTHrP [1][2][3][4][5][6][7][8][9][10][11][12][13][14] have no biological activity, while the trrHrP and PTHrP have 0.01% and 10%, respectively, of the biological activity of PTHrP . The ability of these shorter peptides to stimulate bone resorption has not been assessed.…”

Section: Pth-related Peptidementioning

confidence: 99%

“…Adenylate cyclase stimulating activity is greatly reduced in peptides of less than 30 amino acids. Synthetic analogues of PTHrP can potently increase nephrogenous cyclic AMP and renal phosphate excretion and decrease calcium excretion [12,46]. In addition, binding affinity to renal PTH receptors is comparable to hPTH [49].…”

Section: Pth-related Peptidementioning

confidence: 99%

See 4 more Smart Citations

Hypercalcaemia of malignancy

Kelly

Eisman

1989

Cancer Metast Rev

View full text Add to dashboard Cite

Hypercalcaemia in malignancy is a major clinical problem. It contributes significantly to morbidity and mortality and can present difficult diagnostic and management dilemmas. Direct bony invasion by tumour cells rather than humorally mediated hypercalcaemia is probably the most common cause of malignant hypercalcaemia. Yet even in this situation the mechanism of bone resorption or the reason that the normal homeostatic mechanisms cannot cope with the calcium load are poorly understood. It is likely that the humoral and paracrine factors produced by tumours which result in hypercalcaemia or in osteosclerotic bone metastases, are interposing themselves into the normal regulatory processes and deranging them. Humoral hypercalcaemia of malignancy is an important model for studying these questions, and it also provides some insight into the normal regulation of bone turnover. This review will examine the animal models and human syndromes of malignant hypercalcaemia and show how animal models, although helpful, fail to delineate the relative importance of the various potential humoral factors. A most interesting recent development in this area is the description of a new hormone, the parathyroid hormone-related peptide, which may explain many of the cases of humoral hypercalcaemia of malignancy. It is also a useful model with multiple sites of action within the bone and calcium homeostatic process. The active hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3, may also be involved in a small proportion of cases, but again it is a useful model of some of the factors that may operate. Of considerable interest are the tumour derived factors, such as the transforming growth factors, and the cytokines, such as tumour necrosis factors, interleukins, and haemopoietic colony stimulating factors. Prostanoids are seldom of major importance, but may be important in certain tumour types. Osteosclerotic metastases, although seldom associated with hypercalcaemia, may provide insight into osteoblast regulating factors. Treatment of hypercalcaemia is discussed to show ways in which response to treatment may shed light on underlying pathophysiological mechanisms. Most effective treatments have many potential modes of action, and further study of the interactions of these agents and tumour types may help to unravel some of the enigmas in this human syndrome. The major advances in this complex problem involve the realisation of the necessity of multiple sites of action, including renal calcium handling as well as relative increases in bone resorption and/or intestinal calcium absorption.(ABSTRACT TRUNCATED AT 400 WORDS)

show abstract

Section: Animal Modelsmentioning

confidence: 99%

Section: Animal Modelsmentioning

confidence: 99%

Section: Pth-related Peptidementioning

confidence: 99%

Section: Pth-related Peptidementioning

confidence: 99%

Section: Pth-related Peptidementioning

confidence: 99%

See 3 more Smart Citations

Hypercalcaemia of malignancy

Kelly

Eisman

1989

Cancer Metast Rev

View full text Add to dashboard Cite

show abstract

Contrasting mechanisms of hypercalcemia in patients with early and advanced humoral hypercalcemia of malignancy

Ralston

Cowan

Gardner

et al. 1989

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

The mechanisms of hypercalcemia were assessed in 15 patients with humoral hypercalcemia of malignancy (HHM) who had tumors at various stages of progression. In patients with early tumors, bone biopsies were generally normal and the hypercalcemia was due to an elevation in renal tubular resorption of calcium. Conversely, osteoclastic resorption was markedly increased in patients with advanced tumors, particularly those in whom the biopsies were obtained postmortem. Osteoclast surface (Oc.S) correlated positively with the stage of tumor progression (r = 0.80, p less than 0.002), degree of immobility (r = 0.87, p less than 0.002), and level of urinary cyclic AMP excretion (r = 0.60, p less than 0.02). When compared with a group of ambulant patients with primary hyperparathyroidism (HPT), osteoblast surface (Ob.S%) in HHM was depressed (median and range): 1.2% (0-11.6%) versus 5.3% (1.1-32.0%) (p less than 0.001). However, a relatively low Ob.S (4%) and raised Oc.S (43.5%) were also seen in an immobilized patient with severe HPT. These data suggest that the PTH-related peptides currently invoked in the pathogenesis of HHM may initially cause hypercalcemia by enhancing renal tubular calcium resorption. The increase in osteoclastic activity and depression of osteoblastic activity that subsequently occurs is probably due to the combined effects of immobilization and higher circulating levels of PTHrP on the skeleton. However, the release of other bone-resorbing factors by the tumor, which have a depressant effect on osteoblastic activity, remains possible.

show abstract

Renal cell carcinoma in tissue culture secretes nondialyzable product that stimulates bone resorption in organ-cultured mouse calvaria

Lerner

Ljungberg

1989

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

The bone-resorbing capacity of human renal cell carcinomas in vitro has been examined. Bone resorption in cultures of mouse calvarial bones was assessed by the release of 45Ca from bones prelabeled in vivo and the mobilization of stable calcium and inorganic phosphate from nonlabeled bones. In addition, bone organic matrix degradation was determined either by the release of 3H from [3H]proline-labeled bones or by the loss of hydroxyproline from bone explants during culture. Tumor tissue-conditioned media (TCM) from 13 of 13 renal cell carcinomas stimulated bone resorption in a dose-dependent manner. From 5 of 13 kidneys with renal cell carcinoma, normal kidney cortex tissue was cultured and 4 of these 5 also produced bone-resorbing activity, but the amount was much less compared with the tumor tissue. The stimulatory effect of TCM on 45Ca release could be observed first after 12-24 h of culture. The effect could be inhibited by calcitonin but not by inhibitors of prostaglandin synthesis. The production of bone-resorbing activity by tumor cells could be inhibited by indomethacin and meclofenamic acid. In some tumors, the inhibition by indomethacin was total, whereas in other tumors only partial inhibition could be obtained. In 3 of 4, TCM bone-resorbing activity could be found in the retentate after dialysis. The results show that fresh human renal cell carcinoma tissue can elaborate prostanoid as well as nonprostanoid products that can stimulate bone resorption.

show abstract

Failure of parathyroid hormone antagonists to inhibit in vitro bone resorbing activity produced by two animal models of the humoral hypercalcemia of malignancy.

Abstract: in these two models of HHM, the bone resorbing factors do not exert their effects by interacting with PTH receptors on bone.

Cited by 26 publications

References 11 publications

Hypercalcaemia of malignancy

Hypercalcaemia of malignancy

Contrasting mechanisms of hypercalcemia in patients with early and advanced humoral hypercalcemia of malignancy

Renal cell carcinoma in tissue culture secretes nondialyzable product that stimulates bone resorption in organ-cultured mouse calvaria

Contact Info

Product

Resources

About