Effects of acute and chronic hypercalcemia on parathyroid function and circulating parathyroid hormone molecular forms.

Bas et al. (1), in this issue, have demonstrated that acute hypercalcemic clamp over 2 h in rabbits reduces the subsequent intact (I) parathyroid hormone (PTH) response to hypocalcemia by 50%, while chronic hypercalcemia, secondary to experimental renal failure in the same animal model, fails to reduce the I-PTH response to hypocalcemia. These results raise questions about the acute and chronic influence of calcium concentration on parathyroid function and on circulating PTH molecular forms. To understand and appropriately discuss these differences, it is necessary to review various aspects of PTH physiology. Circulating PTH is immunoheterogenous. Under normocalcemic conditions, it is composed of 20% PTH(1–84), the biologically active form of the hormone on the PTH/PTHrP receptor, and of 80% carboxylterminal (C) fragments, considered until recently to be biologically inactive (2, 3). The main circulating C-PTH fragments observed during the peripheral metabolism of I-bovine (b) PTH(1 –84) in rats start at positions 34, 37 and 39 (4) of the bPTH structure. Porcine (p) parathyroid cells have been demonstrated to secrete pPTH fragments starting at positions 34 and 37 (5). Studies in humans have also outlined the existence of smaller C-PTH fragments (6) and, more recently, of larger C-PTH fragments with a partially preserved aminoterminal structure (7), called non(1 –84)PTH. These non-(1 –84)PTH molecular form or forms have been described in humans during the analysis of normal and abnormal serum HPLC profiles using Nichol’s I-PTH assay (7), the same assay as that employed by Bas et al. (1) in their study. Most I-PTH assays have since been demonstrated to also react with non-(1 –84)PTH (8). Non-(1 –84)PTH accounts for 10% of C-PTH fragments and for 20% of I-PTH immunoreactivity in normal individuals. It is of particular interest because, on theoretical grounds, it could react with the PTH/PTHrP receptor and interfere with the biological effects of PTH(1 –84). Hypercalcemia acutely suppresses PTH secretion to a non-suppressible and detectable PTH concentration (9) while hypocalcemia stimulates PTH secretion to a maximum (9), both stimuli contributing to the sigmoidal relationship between Ca and PTH concentrations (10). Ca concentration also influences PTH secretion qualitatively (2, 3, 11, 12). While suppressing PTH concentration, hypercalcemia favors C-PTH fragment secretion over that of PTH(1–84) (11), C-PTH fragments now accounting for 90% of circulating PTH immunoheterogeneity, and PTH(1 –84) only 10%, causing a high C-PTH/PTH(1–84) ratio in the circulation (2, 3, 12). Hypocalcemia stimulates the secretion of PTH(1 –84) more than that of C-PTH fragments (11), PTH(1 –84) now accounting for 30% of circulating PTH immunoheterogeneity, and C-PTH fragments 70%, causing a low C-PTH/PTH(1 –84) ratio in the circulation (2, 3, 12). This acute control of PTH secretion and of circulating PTH molecular forms is post-translational (13 –15). PTH synthesis always proceeds maximally in the parathyroid glands, and the amount of PTH available for secretion is controlled by a Ca-dependent degradation process (13 –15) involving destruction of secretory granule content in lysosomes and possibly also within secretory granules (16 –18). In rats, the predominance of one type of secretory granule over the other depends on Ca concentration (17). C-PTH fragments are generated and secreted from these processes (19, 20). This type of regulation is rapid (13 –15) and probably best explains the decrease in mean stimulated I-PTH observed by Bas et al. (1) after hypercalcemic clamp in normal rabbits. Similar results have been observed in cows (21), dogs (22) and humans (23). These modifications are of short duration and can be reversed by a hypocalcemic stimulation that is long enough (23). It is unlikely that other mechanisms are involved in this acute regulation of parathyroid function observed by Bas et al. (1) in view of the short time-course of their experimentation. The significance of these quantitative and qualitative changes in parathyroid function and circulating PTH molecular forms may arise from two recent studies (24, 25) where human (h) PTH(7 –84), and other synthetic C-PTH fragments, to a lesser extent, were found to have biological effects of their own and to antagonize some PTH(1 –84) and PTH(1 –34) biological effects. hPTH(7–84) was used in these studies as the only available representative of non-(1 –84)PTH, with hPTH(39–84) and (53 –84) as representatives of other circulating C-PTH fragments. hPTH(7–84) was European Journal of Endocrinology (2002) 146 407–410 ISSN 0804-4643