Definition
Parathyroid hormone (PTH) is secreted by the parathyroid glands as a polypeptide containing 84 amino acids.
Related Peptide
Parathyroid hormone–related peptide (PTHrP), a peptide hormone derived from normal and tumor cells that regulates bone metabolism and vascular tone, is a naturally occurring angiogenesis inhibitor.
Discovery
In 1925, Collip prepared hot hydrochloric acid extracts of the parathyroid glands, an approach which he correctly deduced was needed to free the active substance from other gland stromal components and render it soluble. The author showed that these acid extracts of the parathyroid gland would completely relieve the tetany that followed parathyroidectomy, and established the parathyroids as an endocrine gland which secreted hormone (PTH) 1.
PTHrP was discovered in association with certain types of cancer that caused elevated blood Ca2+ levels (a syndrome called humoral hypercalcemia of malignancy, or HHM) in affected patients 2.
Structural Characteristics
The teleost PTH and PTHrP amino acid sequences contain a hydrophobic presequence and a putative prosequence, indicating that these are secreted peptides. The predicted mature zPTH1 and zPTH2 are 68 and 67 amino acids long, respectively3, whereas the corresponding pufferfish pPTHA and pPTHB mature peptides are 80 and 62 amino acids, respectively4. Among the fish, human, or chicken mature PTHs, the amino acid identity is roughly 20–25%, although the sequence similarity is close to 40%. However, there is high sequence conservation of the first 34 NH2-terminal amino acid residues, and 10 residues are either identical or have undergone conservative substitutions across all PTHs4. Among the conserved residues in the fish PTHs, several are critical for receptor binding and signal transduction 3, 4.
Mode of Action
Parathyroid hormone receptors are G protein-coupled members of the secretin receptor family that interact with the NH2-terminal 34 amino acids of both PTH and PTHrP (PTH1R) or PTH only (PTH2R). The fact that the COOH-terminal regions of PTH and PTHrP have distinct functions from those mediated by the known PTH receptors suggests that other receptors may exist for these fragments 3. PTH and PTHrP bind mammalian PTH1R with indistinguishable affinity, and both ligands stimulate adenosine 3’, 5’-cyclic monophosphate (cAMP) and inositol 1,4,5-trisphosphate (IP3) accumulation with equivalent efficacy 5.
Functions
PTH-rP and osteolytic bone disease (or predominantly osteolytic bone disease): Clinical studies have shown that breast cancer cells produce increased amounts of PTH-rP when they are present in the bone microenvironment6. One of the major mechanisms by which this may occur is by tumor cell production of PTH-rP in bone. This possibly occurs as a consequence of the release of TGF- ß ?by resorbing bone, which enhances PTH-rP production by breast cancer cells. It has been found that by rendering human breast cancer cells unresponsive to TGF- ß ?by stable transfection with a dominant negative TGF- ß receptor, the tumor cells form less bone metastases and secrete reduced amounts of PTH-rP 7. Increased PTH-rP production leads to increased osteoclast formation and bone resorption, which in turn leads to increased amounts of active TGF-b, which subsequently lead to increased amounts of PTH-rP expression by the breast cancer cells.
Indirect Effects of Parathyroid Hormone on Calcium: Parathyroid hormone also affects the metabolism of inorganic phosphorus and probably of magnesium, and in this way produces secondary effects on calcium. The hormone inhibits renal tubular reabsorption of inorganic phosphorus by a direct action on the renal tubules, resulting in an increase in urinary phosphorus and a fall of serum levels. The decrease in serum levels of inorganic phosphorus tends to raise the level of calcium in the serum, by preventing precipitation of calcium phosphate in bone which occurs when the solubility product for calcium and phosphate is exceeded 8. It has been shown that in the rat, parathyroid hormone also influences transport of magnesium. Both parathyroid extract and pure bovine parathyroid hormone produce a fall in excretion of magnesium in the urine, while parathyroidectomy leads to a decrease in serum levels of magnesium 9. These workers suggest that a fall in serum level of magnesium stimulates the parathyroid glands, and the increased secretion of hormone is the cause of the hypercalcaemia which occurs in magnesium-deficient rats. Changes in concentration of magnesium may therefore upset the normal homeostatic control of calcium.
References
1. Collip JB (1925). The extraction of a parathyroid hormone which will prevent or control parathyroid tetany and which regulates the level of blood calcium. J Biol Chem., 63:395-438.
2. Moseley JM, Kubota M, Diefenbach-Jagger H, Wettenhall RE, Kemp BE, Suva LJ, Rodda CP, Ebeling PR, Hudson PJ, Zajac JD, and Martin TJ (1987). Parathyroid hormone-related protein purified from a human lung cancer cell line. PNAS., 84:5048-5052.
3. Gensure RC, Ponugoti B, Gunes Y, Papasani MR, Lanske B, Bastepe M, Rubin DA, Juppner H (2004). Identification and characterization of two parathyroid hormone-like molecules in zebrafish. Endocrinology, 145:1634-1639.
4. Canario AVM, Rotllant J, Fuentes J, Guerreiro PM, Rita Teodosio H, Power DM, Clark MS (2006). Novel bioactive parathyroid hormone and related peptides in teleost fish. FEBS Lett., 580:291–299.
5. Juppner H (1999). Receptors for parathyroid hormone and parathyroid hormone-related peptide: exploration of their biological importance. Bone, 25:87-90.
6. Powell GJ, Southby J, Danks JA, Stillwell RG, Hayman JA, Henderson MA, Bennett RC & Martin TJ (1991). Localization of parathyroid hormone-related protein in breast cancer metastases - increased incidence in bone compared with other sites. Can Res., 51:3059-3061.
7. Yin JJ, Chirgwin JM, Taylor SD, Dallas M, Massague J, Mundy GR & Guise TA (1996). Dominant negative blockade of the transforming growth factor b (TGFb) type II receptordecreases breast cancer-mediated osteolysis. Journal of Bone and Mineral Researc, 11:180.
8. Harrison MT (1964). Interrelationships of vitamin D and parathyroid hormone in calcium homeostasis. Postgrad. Med. J., 40:497-505.
9. Boss M (1963). Parathyroid Hormone and Magnesium Homceo- stasis. Nature, 198:1058.