Parathyroid hormone metabolites in renal failure: bioactivity and clinical implications

Non-(1-84) parathyroid hormones (PTHs) are large circulating carboxyl-terminal PTH (C-PTH) fragments with a partially preserved amino-terminal structure. They were discovered during high-performance liquid chromatography (HPLC) analysis of circulating PTH molecular forms detected by an intact PTH (I-PTH) assay. Like other C-PTH fragments, they accumulate in blood in renal failure and account for up to 50% of I-PTH. They are secreted by the parathyroid glands in humans, and are generated by the peripheral metabolism of hPTH(1-84) in rats. The exact structure of non-(1-84)PTH fragments is not known. To study the possible role of non-(1-84) in PTH biology, hPTH(7-84) has been used as a surrogate, being the only large C fragment available on the market. In anesthetized, thyroparathyroidectomized rats, hPTH(7-84) caused hypocalcemia beyond that induced by surgery. It also blocked the calcemic response to hPTH(1-84) or hPTH(1-34). Other smaller C-PTH fragments, such as hPTH(39-84) and hPTH(53-84), were synergistic to hPTH(7-84) effects. hPTH(7-84) did not bind to the PTH/PTHrP receptor, but only to the C-PTH receptor in ROS 17/2.8 clonal cells, and did not stimulate cyclic adenosine monophosphate (cAMP) production by the same cells, suggesting that its hypocalcemic action was mediated via a receptor different from the PTH/PTHrP receptor, and that the calcium concentration resulted from the sum of the positive effect of hPTH(1-84) on the PTH/PTHrP receptor and of the negative effect of hPTH(7-84) and of C-PTH fragments on the C-PTH receptor. These data will change our understanding of circulating calcium regulation, which must now be viewed as the end result of opposite actions on two PTH receptors. PTH immunoheterogeneity, a highly regulated phenomenon, contributes to this dual biological effect, generating an agonist for the two different receptors. Clinically these results could have some implications in our knowledge of the PTH resistance of renal failure, of renal osteodystrophy, and of certain aspects of the uremic syndrome.