PTH Related Peptide (PTHrp)
Parathyroid hormone related peptide
general information
Parathyroid hormone-associated protein (PTHrP)*3 is a family of protein hormones produced by various tissues in the body and mostly associated with hypercalcemia of malignancy.
PTHrP *1 is most commonly used in hypercalcemic patients with suppressed PTH and suspected malignancy.
PTHrP is found at levels above the reference range in patients with malignancy hypercalcemia with varying frequency depending on the tumor type. It is most common in hypercalcemia in patients with solid tumors and is above the reference range in 85% of such patients with breast tumors, 70% of those with tumors of lung and renal tract origin, and 27% of those with tumors of the gastrointestinal tract.
It has been 20 years since the tumor-associated factor parathyroid hormone-related peptide was identified. Since then, there have been significant changes in the understanding of malignancy-associated hypercalcemic syndromes and the role of this peptide in normal physiology and in this particular pathological setting. Parathyroid hormone-related peptide has become a useful diagnostic tool in the differential diagnosis of hypercalcemia, and approaches to inhibiting its expression or effects by malignant cells hold promise to treat hypercalcemia and osteolysis associated with some cancers.
Parathyroid hormone (PTH), like factors responsible for the syndrome of malignant hypercalcemia, was first proposed by Albright in the 11940s, based on clinical observations in a single patient with hypercalcemia as a result of renal cell carcinoma. Albright suggested that the clinical syndrome in his patient was similar to that of primary hyperparathyroidism and that a PTH-like factor produced by the tumor was responsible for the most likely explanation. This thinking persisted for the next 40 years and, in the 1960s and 1970s, with the detection of PTH and the development of antisera and immunoassays, the search for PTH along with solid tumors. This research had major negative consequences, apart from some confusion caused by the original antiserum used by the RIA to identify PTH, and some researchers have reported that PTH – or at least PTH-like molecules – is produced by tumors associated with malignancy. In retrospect, these analyzes may have poorly recognized the PTH-related peptide (PTHrP), which is closely related to native PTH at its N-terminal end.
The condition was established in the 1980s that patients with malignancy hypercalcemia often have increased nephrogenic cAMP and also have a circulating factor that increases adenylate cyclase activity in cultured bone cells or kidney membranes. It did PTH but clearly not PTH. Thus, it was concluded that instead of natural PTH, a PTH-like factor is produced by tumors associated with hypercalcemia. In the late 1980s, the active principle responsible for this syndrome was identified as PTHrP, a peptide produced by tumors with close homology to PTH in its N-terminal sequence. In fact, PTHrP was found to arise after gene duplication of PTH, after which both gene products evolved independently as two molecules with different structural complexities and control mechanisms. Despite these differences, PTHrP exerts cellular effects through binding and activation of the receptor it shares with PTH, the type 1 PTH receptor.
In the 1990s, other observations of PTHrP suggested that it was responsible not only for squamous cell carcinomas and other tumors associated with the humo-hypercalcemia syndrome of malignancy, but also for breast cancer, and indeed, in some models, breast cancer-associated osteolysis.
After its identification and molecular cloning in the late 1980s, attention turned to the physiological role of PTHrP. Genetic mouse studies, which were widely used in the mid-1990s to characterize the physiological roles of molecules in bone biology, showed that PTHrP was responsible for normal endochondral bone formation and controlled cartilage proliferation in the growth plate. Perichondral cells and chondrocytes synthesize PTHrP at the ends of the cartilage die in the growth plate. PTHrP inhibits chondrocyte differentiation, thereby delaying the appearance of postmitotic hypertrophic chondrocytes. PTHrP expression in the growth plate is controlled by Indian Hedgehog and downstream mediators in the Gli family via a negative feedback relationship. The Gs and Gg families of heterotrimeric G proteins limit the effects of PTHrP on chondrocytes by their repression by the downstream cyclin-cdk inhibitor p57 and the transcription factor Sox9 to maintain chondrocyte proliferation. These effects of PTHrP on the growth plate appear to serve its essential physiological role.
PTHrP has been shown to play a local role in normal osteoblast function. Osteoblast-specific ablation of PTHrP in mice results in osteoporosis and impaired bone formation suggestive of a paracrine function. Therefore, PTHrP can regulate normal osteoblast (and possibly osteoclast) differentiation and activity in bone osteoblast, and PTHrP is under development as a potential anabolic agent for osteoporosis with bone stimulating effects similar to that of PTH. It also has other local cytokine-type roles of uncertain significance, including the breast, urinary bladder, uterus, vascular smooth muscle, hair follicles, and skin. It also ensures the transfer of calcium from the mother to the fetus across the placenta. Multiple fragments of PTHrP with biological activities have been described, but none of them have been confirmed as either physiological or significant in vivo and remain controversial and remain the subject of research.
Our concepts of the hypercalcemia syndrome of malignancy have changed significantly with the observations that PTHrP plays an important role in humoral hypercalcemia of malignancy and localized osteolysis associated with metastatic cancer. Until the mid-1990s, humoral hypercalcemia of malignancy was thought to be due to a circulating factor (ie PTHrP) and localized osteolysis was thought to result either from local cytokines or from the direct effects of tumor cells causing localized bone destruction. With the observation that PTHrP may be responsible for both syndromes, at least in many patients, the hypercalcemia of malignancy may occur when some tumor is overproduced (and thus causes humoral hypercalcemia) but in other cases when produced by metastatic tumor cells in the bone microenvironment and leads to osteolytic bone metastases. acts as a local factor when
Tumor syndromes associated with PTHrP production
Although PTHrP and PTH share the same receptor, there are differences between humoral hypercalcemia syndromes of malignancy and primary hyperparathyroidism. In humoral hypercalcemia of malignancy, bone formation is suppressed and patients experience a metabolic alkalosis rather than hyperchloremic acidosis. In addition, serum 1,25-dihydroxyvitamin D 3 concentrations are increased in primary hyperparathyroidism and suppressed in cancer. The reasons for these differences are unknown, but may be due to other factors co-produced with PTHrP in humoral hypercalcemia of malignancy.
Other cancer syndromes are associated with excess PTHrP. Probably the most important of these is cachexia, highlighted by Ogata and colleagues. Humoral hypercalcemia of malignancy causes accumulation of orixegenic peptides such as neuropeptide Y in the arcuate nucleus of the hypothalamus, and both cachexia and mRNA for these peptides are reduced by anti-PTHrP treatments. It is still unclear whether cachexia is actually directly due to PTHrP or is the result of increased tumor burden in the bone marrow.
Since PTHrP is an important factor in causing these common malignancy-related syndromes, different attempts have been made to block its biological activity. One approach was the development of neutralizing antibodies to PTHrP based on preclinical studies showing that neutralizing antibodies reduce serum calcium and reduce bone metastasis in preclinical models. Small molecules that inhibit PTHrP transcription per second were used. We identified specific small molecules that inhibit PTHrP transcription by tumor cells. These molecules, which are antimetabolites and contain 6-thioguanine, were identified in a cell-based screening analysis and found to reduce osteolysis and lower serum calcium in preclinical models of bone metastasis and hypercalcemia. The third was to develop antagonists of PTHrP that bind to the PTH receptor, but this has not led to successful therapeutics to date. Other possibilities include small molecule approaches to inhibit PTHrP signaling in tumor cells.
The regulation of PTHrP production by malignant cells is of extreme interest. Why do some cancer cells express a physiologically important peptide in the cartilage cells of the growth plate? In the growth plate, PTHrP is regulated by the Hedgehog pathway and the Gli family of transcriptional mediators. We believe that similar mechanisms, albeit slightly more complex, are also involved in cancer. In solid tumors associated with PTHrP expression, PTHrP transcription was found to be driven by Gli family members similar to that in the developing growth plate. The cancer cell uses the often dormant developmental Hedgehog pathway, important in embryonic life, to increase PTHrP expression, initiate bone resorption, and establish a nidus for bone metastasis. The process is driven by TGF-β, which is released into the bone microenvironment when bone is resorbed because it is the most abundant growth factor in the bone matrix. This adds another level of understanding to the vicious circle between tumor cells and osteoclasts in the bone microenvironment in metastatic cancer. Thus, TGF-γ released as a result of bone resorption in the bone microenvironment induces PTHrP expression and bone resorption, stimulating the expression of Gli family members in the Hedgehog pathway. Bone resorption facilitates tumor cell growth and release of active TGF-γ from the bone matrix.
Pathological roles of PTHrP. PTHrP is a major factor in cancer-associated bone disease responsible for humoral hypercalcemia of malignancy and localized osteolysis. In the latter case, severe bone loss is initiated and triggered by a ‘vicious circle’, thereby stimulating tumor-derived PTHrP osteoclastic resorption. Subsequent release of bone-derived growth factors stimulates tumor growth and expression of PTHrP by tumor cells.
PTHrP is therefore a very interesting molecule. Derived from the same ancestral gene as PTH, it has a limited physiological role to regulate cartilage growth in the development of long bones in embryonic and early postnatal life. It does not play an important physiological role in our knowledge of adult life; however, it has an important pathological role in mediating bone destruction and hypercalcemia by some tumors that learn to activate the developmental hedgehog pathway and express PTHrP allowing tumor cells to establish a “safe haven” in the form of bone metastasis. . As our knowledge of this intriguing process by which cancer destroys bone grows, it seems certain that successful pharmacological treatments seek to limit PTHrP expression or that its effects offer potential benefits for patients with advanced cancer.
Why is PTH Related Peptide (PTHrp) desirable?
As an aid in the evaluation of patients with hypercalcemia of unknown origin
As an aid in the evaluation of patients with humoral hypercalcemia with suspected malignancy.
Notes
SAMPLE COLLECTION PROCEDURES
USERS should contact the Istanbul Laboratory before collecting the sample in order to obtain the PTHrP collection tubes. Tubes should be stored on ice prior to collection and transported to the laboratory on ice immediately after collection – samples must be processed within 30 minutes of collection.
LABORATORY: PTHrP collection tubes are obtained from our laboratory. Samples are kept in the freezer for a while. Search for more tubes when only one remains.
Samples should be rotated at 4 °C immediately after collection and plasma frozen at -20 ºC.
PTHrP samples must be sent to our laboratory by courier frozen on dry ice (same day delivery). Do not send waiting.
Hemolyzed, lipemic, unfrozen samples are not suitable for PTHrP analysis.
The reference range
<or = 4.2 pmol/L
Example: Edtal Plasm Related Tests
Parathyroid Hormone (PTH)
Created Date Record
08 August 2015
last updated date
January 18, 2019
Review date
07.09.2019