Circulating Forms of Parathyroid Hormone: Peeling Back the Onion

Abstract

Circulating parathyroid hormone (PTH) regulates normal bone and mineral ion homeostasis and is central in the pathogenesis of bone disease in primary and secondary hyperparathyroidism, especially in advanced renal insufficiency (1). The major biological effects of PTH, a linear polypeptide 84 amino acids in length, reflect activation of the G-protein-coupled PTH/PTHrP receptor (PTHR) expressed on target cells in the renal tubules and the osteoblastic lineage of bone (2). Activation of PTHRs requires only the most N-terminal portion of PTH [PTH(1–34) is a full agonist] and is mostly eliminated if the N-terminal serine residue of the human hormone is removed. PTH, secreted by the parathyroid glands primarily in response to changes in blood ionized calcium, undergoes rapid endopeptidic cleavage, mainly by Kupffer cells in the liver (3). This event generates a series of N-truncated “CPTH” fragments (the corresponding N-terminal segments are destroyed in situ) that reenter the circulation and are cleared mainly by glomerular filtration, an important route for PTH clearance as well (4). Chemical analysis of PTH fragments isolated from rat blood after administration of radiolabeled bovine PTH established that hepatic metabolism yields a family of CPTH fragments with NH2 termini ranging between residues 34 and 43, although the methods used likely would not have detected substantially larger CPTH fragments (5). Interestingly, chemically similar CPTH fragments are secreted directly from the parathyroid glands as well, and the ratio of secreted CPTH fragments to intact PTH increases as blood calcium increases (6)(7). CPTH fragments typically circulate at a three- to fivefold molar excess over intact PTH, but this ratio may increase dramatically in end-stage renal disease (ESRD), depending on the severity and chronicity of renal insufficiency and the blood concentrations of calcium, phosphate, and 1,25-dihydroxyvitamin D, all of which regulate PTH secretion (1)(8). Measurement of …