PTHrP

May be superior to bisphosphonates for humoral hypercalcemia of malignancy (PTHrp)... 

FIGURE 96-4. Pathophysiology of the hypercalcemia of malignancy. PTHrP, parathyroid hormone-related protein TGF-P, transforming growth factor P TNF-a, tumor necrosis factor alpha Ca2+, calcium IL-1, interleukin 1 IL-2, interleukin 2. 

PTHrP). This protein mimics the action of endogenous parathyroid hormone on bones. Local osteolytic activity causes 20% to 30% of hypercalcemia cases, although local osteolytic activity also may have a humoral component. Local production of various factors directly stimulates osteoclastic... 

Interleukin-6 (IL-6) is a member of the gpl30 cytokine family and is con-stitutively produced by several cells of bone microenvironment, particularly by osteoblasts and their precursors (Heymann et al. 2000). The main function in bone is on OCS and bone resorption, and its effects are connected to those of IL-1, TNF-a, and PTHrP. IL-6 induces osteoclastlike formation by inducing IL-1 synthesis, and the addition of anti-IL-1 inhibits osteoclast formation by IL-6 (Kurihara et al. 1990). Moreover, IL-6 mediates the effects of TNF-a and enhances PTHrP-induced hypercalcemia and bone resorption by increasing the osteoclast progenitor pool and differentiation into mature osteoclasts (Devlin et al. 1998). 

Independently, if these cytokines can exert their bone resorption functions without RANKL, they all stimulate the production of RANKL for stromal/OB cells, and conversely RANKL is able to increase IL-1 and TNF-a synthesis in vitro. To complicate this scenario, these systems of cytokines connect with the network of systemic hormones, such as PTH, PTH-related protein (PTHrP), vitamin D3, estrogens, androgens, glucocorticoids, and T4, since the hormones regulate the production of many of these cytokines by stromal/OB cells (Manolagas et al. 1995 Bellido et al. 1995 Lakatos et al. 1997). 

Devlin RD, Reddy SV, Savino R, Ciliberto G, Roodman GD (1998) IL-6 mediates the effects of IL-1 or TNF, but not PTHrP or l,25(OH)2D3, on osteoclast-like cell formation in normal human bone marrow cultures. J Bone Miner Res 13 393-399... 

PTHrP). The receptor signal is mediated by G proteins that activate adenylyl cyclase and the phosphatidylinositol-calcinm second-messenger system. Mntations of PTHRl are associated with abnormalities of development related to altered PTHrP ligand binding. PTHrP is a key paracrine peptide responsible for osteochondrogenesis dnring fetal development (55,56). 

PTH is a single-chain polypeptide composed of 84 amino acid residues that is devoid of disulfide bonds and has a molecular weight of 9500. Biological activity of the human hormone resides primarily in the amino terminal end of the protein (i.e., amino acids 1-34). This portion of PTH has full biological activity both in vivo and in vitro. Synthetic fragments of the 1-34 portion of the PTH molecule have been synthesized. A paraneoplastic hormone, PTH related peptide (PTHrP) has been identified, isolated, and synthesized. PTHrP is... 

Human rPTH (1-34) has been produced by recombinant technologies, is now approved, and will soon be available for the treatment of osteoporosis. It is given subcutaneously, 25 Jig/day cyclically for 12 to 18 months, to increase bone density in individuals with a history of fractures, severe osteopenia, or osteoporosis. PTHrP (1-36) has also been synthesized and is in early clinical trials. 

Plotkin H et al. Dissociation of bone formation from resorption during two-week treatment with PTHrP (1-36) in humans Potential anabolic therapy for osteoporosis. J Clin Endocrinol Metab 1998 83 2786-2791. 

The authors suggested that this was the first report of exogenous calcitonin causing hypercalcemia. There were several unknowns in this case, including the calcium concentration before treatment and the concentration of PTHrp, which would have helped to determine the cause of the hypercalcemia. Calcitonin is usually associated with a reduction in calcium concentration rather than a rise. The authors postulated that calcitonin could alter PTHrp concentrations, with different effects depending on cell type. They also provided evidence of hypercalcemia caused by calcitonin in non-human models (14). 

Sanders, JL, Chattopadhyay, N, Kifor, O, Yamaguchi, T and Brown, EM, 2000, Extracellular calciumsensing receptor (CaR) expression and its potential role in parathyroid hormone-related peptide (PTHrP) secretion in the H-500 rat Ley dig cell model of humoral hypercalcemia of malignancy, Biochem Biophys Res Commun 269 127 132... 

Iwamura M, Heilman J, Cockett AT, Lilja H, Gershagen S. Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen. Urology 1996 48 317-325. 

Parathyroid hormone-related protein (PTHrP)] (protein)... 

Sox4 a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins, such as syndecan binding protein (syntenin). The protein may also function in the apoptosis pathway leading to cell death as well as to tumorigenesis and may mediate downstream effects of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in bone development. 

Hypercalcemia occurs in 10% to 20% of individuals with cancer. Tumors most commonly cause hypercalcemia by producing PTHrP, which is secreted into the circulation and stimulates bone resorptions and/or by invasion of the bone by metastatic tumor, which produces local factors that stimulate bone resorption. PTHrP binds to the PTH receptor and is the principal mediator of humoral hypercalcemia of malignancy (HHM). Cytokines such as lymphotoxin, interleukin-1, tumor necrosis factor, and PTHrP appear to be important mediators of hypercalcemia in multiple myeloma and other hematological malignancies. Some lymphomas associated with acquired immunodeficiency syndrome or HTLV [ infections cause hypercalcemia by producing 1,25(0H)2D. It is estimated that 5% of patients with hypercalcemic cancer have coexisting primary hyperparathyroidism. 

Laboratory test selection is similar to that in suspected hyperparathyroidism, with the addition of PTHrP in some individuals with HHM. In specific instances (for example, lymphoma), measurement of 1,25(OH)2D may be useful,... 

PTH and 1,25-dibydroxyvitamin D are the primary hormones regulating bone and mineral metabolism. Calcitonin has pharmacological actions, but a physiological role has not been established in adults. PTHrP is the principal mediator of hmnoral hypercalcemia of malignancy. 

Recent studies have suggested that N-terminal-truncated PTH may be biologically active. Synthetic PTH(7-84), used as the available representative of N-terminal-truncated PTH, decreased serum calcium antagonized the calcemic, phosphatemic, and phosphaturic effects of intact PTH in thyroparathyroidectomized animals and was bound by a C-terminal PTH receptor distinct from the PTH/PTHrP receptor. ... 

Parathyroid Hormone-Related Protein PTHrP was discovered in 1987 by investigators studying the mechanism by which certain cancers produce humoral hypercalcemia of malignancy (HHM). ... 

The common N-terminal explains the ability of PTHrP to interact with the PTH/PTHrP receptor, mimicking the biological actions of PTH in classic target tissues, including bone and kidney. Like PTH, PTHrP causes hypercalcemia and hypophosphatemia t and increases urinary cyclic AMP. However, when compared with patients with primary hyperparathyroidism, patients with PTHrP-induced hypercalcemia have lower concentrations of l,25(OH)2D and more typically have metabolic alkalosis (instead of hyperchloremic metabolic acidosis), reduced distal tubular calcium reabsorption, and reduced and uncoupled bone formation. 

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