scholarly journals Conflicting actions of parathyroid hormone-related protein and serum calcium as regulators of 25-hydroxyvitamin D(3)-1 alpha-hydroxylase expression in a nude rat model of humoral hypercalcemia of malignancy

2001 ◽  
Vol 171 (2) ◽  
pp. 249-257 ◽  
Author(s):  
T Michigami ◽  
H Yamato ◽  
H Suzuki ◽  
Y Nagai-Itagaki ◽  
K Sato ◽  
...  
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Vitamin D Metabolism ◽  
Hydroxyvitamin D ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Severe Hypercalcemia ◽  
25 Hydroxyvitamin D

In patients with humoral hypercalcemia of malignancy (HHM), serum levels of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) are generally low, although the pathophysiology of the impaired vitamin D metabolism is not fully understood. In the present study, we have investigated vitamin D metabolism in our newly developed rat model of HHM in which a human infantile fibrosarcoma producing parathyroid hormone-related protein (PTHrP), named OMC-1, was inoculated s.c. into athymic nude rats. In OMC-1-bearing rats, the serum concentration of 1,25(OH)(2)D was markedly reduced when the animals exhibited severe hypercalcemia (Ca > or =15 mg/dl), while it was rather elevated in those with mild hypercalcemia. To further examine whether serum Ca levels affect 1,25(OH)(2)D concentration, we administered bisphosphonate YM529 to OMC-1-bearing rats when they exhibited severe hypercalcemia. The restoration of the serum Ca level by administration of YM529 was accompanied by a marked increase in the 1,25(OH)(2)D level, suggesting that the serum Ca level itself plays an important role in the regulation of the 1,25(OH)(2)D level in these rats. On the other hand, when the OMC-1-bearing rats were treated with a neutralizing antibody against PTHrP, serum 1,25(OH)(2)D levels remained low despite the reduction in serum Ca levels. Expression of 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) in kidney was decreased in OMC-1-bearing rats with severe hypercalcemia, and markedly enhanced after treatment with bisphosphonate. This enhancement in 1 alpha-hydroxylase expression was not observed after treatment with the antibody against PTHrP. These results suggest that PTHrP was responsible for the enhanced expression of 1 alpha-hydroxylase in YM529-treated rats, and that hypercalcemia played a role in reducing the serum 1,25(OH)(2)D level in OMC-1-bearing rats by suppressing the PTHrP-induced expression of the 1 alpha-hydroxylase gene.

Elevated parathyroid hormone-related protein and hypercalcemia in two dogs with schistosomiasis

2001 ◽  
Vol 37 (4) ◽  
pp. 349-355 ◽  
Author(s):  
JM Fradkin ◽  
AM Braniecki ◽  
TM Craig ◽  
F Ramiro-Ibanez ◽  
KS Rogers ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Granulomatous Inflammation ◽  
Clinical Findings ◽  
Diagnostic Evaluation ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Fecal Examination ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Clinicopathological Findings

Two adult dogs were evaluated for hypercalcemia. Diagnostic evaluation identified elevated parathyroid hormone-related protein (PTHrP) and presumptive humoral hypercalcemia of malignancy. At necropsy, schistosomiasis was diagnosed. North American schistosomiasis is caused by Heterobilharzia americana. Clinical findings may include dermatitis, coughing, diarrhea, and anorexia. Clinicopathological findings may include hypercalcemia, hyperglobulinemia, hypoalbuminemia, anemia, and eosinophilia. Diagnosis by fecal examination is difficult. Praziquantel or fenbendazole treatment may be curative or palliative. These are the first reported cases of hypercalcemia with elevated PTHrP in animals without diagnosed malignancy. Elevation of PTHrP has not been previously reported in hypercalcemic humans or in animals with granulomatous inflammation.

Defining the roles of parathyroid hormone-related protein in normal physiology

1996 ◽  
Vol 76 (1) ◽  
pp. 127-173 ◽  
Author(s):  
W. M. Philbrick ◽  
J. J. Wysolmerski ◽  
S. Galbraith ◽  
E. Holt ◽  
J. J. Orloff ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Fetal Life ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Physiological Functions ◽  
Hypercalcemia Of Malignancy ◽  
Normal Tissues ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Differentiation And Proliferation

Parathyroid hormone-related protein (PTHrP) was discovered as a result of a search for the circulating factor secreted by cancers which causes the common paraneoplastic syndrome humoral hypercalcemia of malignancy. Since the identification of the peptide in 1982 and the cloning of the cDNA in 1987, it has become clear that PTHrP is a prohormone that is posttranslationally cleaved by prohormone convertases to yield a complex family of peptides, each of which is believed to have its own receptor. It is also clear that the PTHrP gene is expressed not only in cancers but also in the vast majority of normal tissues during adult and/or fetal life. In contrast to the situation in humoral hypercalcemia of malignancy in which PTHrP plays the role of a classical "endocrine" hormone, under normal circumstances PTHrP plays predominantly paracrine and/or autocrine roles. These apparent physiological functions are also complex and appear to include 1) regulation of smooth muscle (vascular, intestinal, uterine, bladder) tone, 2) regulation of transepithelial (renal, placental, oviduct, mammary gland) calcium transport, and 3) regulation of tissue and organ development, differentiation, and proliferation. In this review, the discovery of PTHrP, the structure of its gene and its cDNAs, and the posttranslational processing of the initial translation products are briefly reviewed. Attention is then focused on a detailed organ system-oriented review of the normal physiological functions of PTHrP.

A Parathyroid Hormone–Related Protein–Secreting Metastatic Epithelioid Leiomyosarcoma

2003 ◽  
Vol 127 (4) ◽  
pp. e181-e185
Author(s):  
Shou-jiang Tang ◽  
Sunil Geevarghese ◽  
Sammy Saab ◽  
Dorothy Martinez ◽  
Andre Van Herle ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Tumor Resection ◽  
Smooth Muscle Tumor ◽  
Uterine Leiomyosarcoma ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Uterine Tumor ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Calcium Phosphorus

Abstract A diagnosis of parathyroid hormone–related protein (PTH-rP)–secreting metastatic uterine epithelioid leiomyosarcoma was made in a 61-year-old woman with humoral hypercalcemia of malignancy. A primary uterine tumor had been removed 10 years previously, which had been associated with a short history of hypercalcemia. The original uterine tumor was diagnosed as a smooth muscle tumor of uncertain malignant potential. To the best of our knowledge, this is the first reported case of a PTH-rP–secreting uterine leiomyosarcoma. We demonstrate the dramatic changes in serum calcium, phosphorus, PTH, and PTH-rP levels after tumor resection. Extensive biochemical analysis and detailed immunohistochemical and ultrastructural characterization demonstrate several features of this tumor.

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