Toward an Understanding of Human Parathyroid Hormone Structure and Function

Abstract

PTH and Its Receptor Family P arathyroid hormone (PTH) is synthesized as a 115 amino acid precursor and secreted as an 84 amino acid polypeptide that regulates extracellular calcium homeostasis via actions directly on kidney and bone and indirectly on the intestine by facilitating calcium absorption. PTH and a related molecule, parathyroid hormone-related protein (PTHrP), act on cells via a common G protein-coupled, seven-transmembrane helix receptor (PTH/ PTHrP or PTHl receptor)."^ PTH has both anabolic and catabolic effects on the skeleton. Persistent elevation of plasma PTH causes predominately increased bone resorption, whereas intermittently administered PTH results in enhanced bone formation.^' The mechanism by which PTH exhibits its dual effects is not fully known. PTH interacts with the PTH 1 receptor to stimulate adenylyl cyclase (AC) (5) and phospholipase C (PC) pathways. The naturally occurring hPTH(l-37) fragment as well as hPTH(l-34) maintains the full spectrum of bone-relevant activities of the intact 1-84 hormone. Studies, both in vitro and in vivo, have shown that hPTH(l-34) has the same biological activities as the intact hormone in eliciting cAMP responses and in stimulating bone formation.^ Thus hPTH(l-34) has all the structural elements necessary for binding and activation of the PTHl receptor. Once daily subcutaneous administration of hPTH(l-34) stimulates bone formation and increases bone mass in patients with osteoporosis and in ovariectomized monkeys.^ Consequently, hPTH(l-34) represents a novel class of therapeutics for the treatment of osteoporosis.^'^ Truncation and mutagenesis studies on PTH(l-34) have revealed that the N-terminal region of the peptide is critical for full activation of receptor signaling, while the N-terminal truncated peptide PTH (3-34) is a partial agonist, and the further shortened peptide PTH (7-34) becomes a low affinity antagonist. ' ^ Residues 17 to 31, near the C-terminus of PTH (1-34), are required for high affinity receptor binding. PTHrP is over-expressed in certain tumors and causes the syndrome of malignancyassociated humoral hypercalcemia.^^ Under physiological conditions, PTHrP is produced locally in a wide variety of tissues and is involved in cell growth, differentiation, and development of the skeleton. There are six identical amino acids in the first 13 amino acids in the known PTH and PTHrP sequences (Fig. 1). Like PTH, PTHrP binds to the same G protein-coupled receptor, and its N-terminal fragment PTHrP(l-34) has many functions that mimic those of