Increased Renal Calcium Reabsorption by Parathyroid Hormone–Related Protein Is a Causative Factor in the Development of Humoral Hypercalcemia of Malignancy Refractory to Osteoclastic Bone Resorption Inhibitors

2005 ◽  
Vol 11 (11) ◽  
pp. 4198-4203 ◽  
Author(s):  
Etsuro Onuma ◽  
Yumiko Azuma ◽  
Hidemi Saito ◽  
Toshiaki Tsunenari ◽  
Toshihiko Watanabe ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Bone Resorption ◽  
Causative Factor ◽  
Osteoclastic Bone Resorption ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Hypercalcemia Of Malignancy ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Calcium Reabsorption

scholarly journals Parathyroid Hormone-Related Protein-(1–36) Stimulates Renal Tubular Calcium Reabsorption in Normal Human Volunteers: Implications for the Pathogenesis of Humoral Hypercalcemia of Malignancy1

2001 ◽  
Vol 86 (4) ◽  
pp. 1525-1531 ◽  
Author(s):  
Mushtaq A. Syed ◽  
Mara J. Horwitz ◽  
Mary Beth Tedesco ◽  
Adolfo Garcia-Ocaña ◽  
Stephen R. Wisniewski ◽  
...  
Keyword(s):  
Steady State ◽  
Bone Resorption ◽  
Healthy Volunteers ◽  
Osteoclastic Bone Resorption ◽  
Calcium Excretion ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Calcium Reabsorption

All would agree that hypercalcemia occurs among patients with humoral hypercalcemia of malignancy (HHM) as a result of osteoclastic bone resorption. Some studies suggest that enhanced renal calcium reabsorption, which plays an important pathophysiological role in the hypercalcemia occurring in primary hyperparathyroidism, is also important pathophysiologically in HHM. Other studies have not agreed. In large part, these differences result from the inability to accurately assess creatinine and calcium clearance in critically ill subjects with HHM. To circumvent these issues, we have developed steady state 48-h PTH-related protein (PTHrP) infusion and 8-h hypercalcemic calcium clamp protocols. These techniques allow assessment of the effects of steady state PTHrP and calcium infusions in normal healthy volunteers in a setting in which renal function is stable and measurable and in which the filtered load of calcium can be matched in PTHrP- and calcium-infused subjects. Normal subjects were infused with saline (placebo), PTHrP, or calcium. Subjects receiving PTHrP, as expected, displayed mild hypercalcemia (10.2 mg/dL), suppression of endogenous PTH-(1–84), and phosphaturia. Subjects receiving the hypercalcemic calcium clamp displayed indistinguishable degrees of hypercalcemia and PTH suppression. Despite their matched degrees of hypercalcemia and PTH suppression, the two groups differed importantly with regard to fractional calcium excretion (FECa). The hypercalcemic calcium clamp group was markedly hypercalciuric (FECa averaged 6.5%), whereas FECa in the PTHrP-infused subjects was approximately 50% lower (between 2.5–3.7%), and no different from that in the normal controls, which ranged from 1.5–3.0%. These studies demonstrate that PTHrP is able to stimulate renal calcium reabsorption in healthy volunteers. These studies suggest that PTHrP-induced renal calcium reabsorption, in concert with the well established acceleration of osteoclastic bone resorption, contributes in a significant way to the hypercalcemia observed in patients with HHM.

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.

Parathyroid Hormone-Related Protein: Structure, Function, and Measurement

1992 ◽  
Vol 38 (11) ◽  
pp. 2171-2183 ◽  
Author(s):  
W J Burtis
Keyword(s):  
Parathyroid Hormone ◽  
Amino Acid ◽  
Amino Acid Sequences ◽  
Related Protein ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Hypercalcemia Of Malignancy ◽  
Physiological Importance ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Order Of Magnitude

Abstract Parathyroid hormone-related protein (PTHRP) is a 139- to 173-amino-acid protein with N-terminal homology to parathyroid hormone (PTH). Initially isolated from tumors from patients with humoral hypercalcemia of malignancy, PTHRP appears to be of far more widespread physiological importance. Its complex gene is expressed in a surprising diversity of tissues. The primary amino acid sequences of both the PTH-like and non-PTH-like regions of the protein are highly conserved across species. In addition to classical and nonclassical PTH-like activities of the N-terminal region, other biological functions have been ascribed, including augmentation of calcium transport by midregion PTHRP and potent inhibition of bone resorption by a C-terminal peptide. There is emerging evidence that the protein undergoes extensive processing, including glycosylation and defined proteolytic cleavages. Several region-specific immunoassays are now capable of measuring circulating concentrations of PTHRP in patients with humoral hypercalcemia of malignancy. Molar concentrations of different regions may differ by more than an order of magnitude, reflecting diversity in processing and (or) metabolism. By analyzing the results of these assays, taking into account the specificities of known endoproteases, one can hypothesize about some of the endoproteolytic cleavages that occur in PTHRP metabolism. Clinically, selected PTHRP assays can be very helpful in diagnosing PTHRP-mediated hypercalcemia, but are not yet sufficiently sensitive to accurately measure normal concentrations of the protein.

Sign in / Sign up

Export Citation Format

Share Document