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

Abstract

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 125 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 2+ and PTH concentrations (10). Ca 2+ 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 amoun...

Dynamics of Parathyroid Hormone Secretion in Health and Secondary Hyperparathyroidism

“…The serum calcium response to PTH (curve 1) is almost linear between 5 and 10 mg/dl, but the calcemic response to PTH decreases when the serum calcium exceeds 10 mg/dl. Reasons for the decreased calcemic response to PTH above a serum calcium of 10 mg/dl include (1) the greater gradient of calcium against which PTH must function; (2) the decrease in serum phosphorus is maximal at PTH values two to three times normal and does not decrease much more at higher PTH values (2); (3) the deterioration in renal function resulting from hypercalcemia decreases phosphorus excretion, which, in turn, increases the serum phosphorus concentration, thereby compromising the calcemic action of PTH (2-4); and (4) the proportional increase in the percentage of carboxy-terminal and large truncated amino-terminal PTH fragments of which 7-84 PTH is the prototype (5,6). These PTH fragments seem to antagonize the calcemic action of PTH by binding to the carboxy-terminal PTH (C-PTH) receptor (7)(8)(9) and possibly by inducing internalization of the PTH1 receptor (10).…”

“…The amount of PTH available for secretion is controlled by an intraglandular calcium-dependent degradation process (5). Acute hypercalcemia is known to increase the relative proportion of C-PTH and 7-84 PTH fragments as compared with 1-84 PTH (6,21).…”

Cinacalcet Reduces the Set Point of the PTH-Calcium Curve

“…20 This reduced response is due, in part, to an increase in carboxy-terminal and large truncated amino-terminal PTH fragments. 25,26 These fragments antagonize the calcemic effect of PTH. 10,27,28 Some authors proposed that a decrease in wPTH/non-wPTH ratio was associated with decreased turnover.…”

Carboxyl-terminal parathyroid hormone fragments: role in parathyroid hormone physiopathology

“…This has promoted the belief that the C-sequence of PTH is inactive. Paradoxically, circulating PTH does not reflect this biological reality and is mainly composed of C-PTH fragments [9]. These fragments are well regulated but their biological effects have been difficult to uncover because a different PTH receptor appears to be involved [9].…”

“…Paradoxically, circulating PTH does not reflect this biological reality and is mainly composed of C-PTH fragments [9]. These fragments are well regulated but their biological effects have been difficult to uncover because a different PTH receptor appears to be involved [9]. Data on the nature and regulation of C-PTH fragments, their biological effects and their clinical importance constitute the central theme of this review.…”