Differences in PTH (1–84) release in response to ambient calcium concentrations of parathyroid adenoma fragments and dispersed parathyroid adenoma cells in culture

Abstract

In a previous study we observed that during perfusion of normal human parathyroid tissue, the release of PTH (1-84) was modulated by ambient extracellular calcium (Ca++) and lithium (Li+) concentrations in the media and preliminary studies indicated that this stimulus-response coupling was absent in human parathyroid adenoma fragments. The present study compares the responsiveness of parathyroid adenoma fragments and isolated parathyroid adenoma cells from the same adenoma and their response to Ca++ changes and Li+ presence in culture media. The data indicate that parathyroid adenoma tissue fragments fail to respond to ambient changes in Ca++ and Li+. In contrast, dispersed parathyroid cells preparations responded with a significant increase of PTH (1-84) release (50%) under the influence of low ambient calcium concentrations. Six of the dispersed cell preparations also responded with a 45% decrease in PTH release under the influence of a high Ca concentration in the medium. Isolated parathyroid cells obtained from the same adenoma's did not respond to the presence of Li++ in the medium. These data suggest tat human parathyroid adenoma tissue functions autonomously and is not sensitive to calcium regulation in the tissue configuration as opposed to the isolated cell suspensions. The nature of this difference remains elusive.

Glandular regulation of interstitial diffusion: a model and simulation of a novel physiological mechanism

“…The PTH output is robust with respect to ␣ and V. Note the sensitivity of the output P (PTH) to small changes in cell threshold level, a feature of the model consistent with observed physiology (4). surrounding normal cells suggest relatively suppressed PTH levels, a physiology consistent with that seen in clinical experience (8,11,16,40). In vitro experimental evidence of this effect is suggested in Yu et al (40), who showed that adenomatous cells, although residing in a connected group, persisted in PTH secretion at a given calcium concentration that was subsequently inhibitory to the same group after their dispersal into smaller groups.…”

“…surrounding normal cells suggest relatively suppressed PTH levels, a physiology consistent with that seen in clinical experience (8,11,16,40). In vitro experimental evidence of this effect is suggested in Yu et al (40), who showed that adenomatous cells, although residing in a connected group, persisted in PTH secretion at a given calcium concentration that was subsequently inhibitory to the same group after their dispersal into smaller groups. Additional experimental support is found in Sun et al (34), who showed that denser cell collections on average secreted more PTH.…”

“…The mechanisms that enable this endocrine cell network to coordinate a collective response are largely unknown. Calcium binding to the extracellular domain of a calcium-sensing receptor is thought to inhibit the exocytosis of stored PTH (40). In vitro studies have shown that denser collections of PTHproducing cells secrete more PTH per unit cell than sparse collections and that this effect was not due to conditioned media (10,34).…”

“…In vitro studies have shown that denser collections of PTHproducing cells secrete more PTH per unit cell than sparse collections and that this effect was not due to conditioned media (10,34). Studies in vivo and in vitro have shown that PTH-secreting tumors (adenoma) maintain higher PTH secretion than healthy tissue (3), whereas calcium's regulatory effect on this secretion is significantly dampened (28,40). However, calcium sensitivity is at once recovered in vitro when the adenoma is dispersed into smaller cellular collections (28).…”

“…In this configuration, the cell network is poised to tune its own secretory response by locally controlling molecular diffusion. A compelling consequence of this theory is that altered geometry and deficient or ineffective calcium-sensing receptors in adenomatous and hyperplastic cells would establish and maintain a higher intercellular protein concentration and dampen the regulatory effects of calcium, as is observed in vivo and in vitro (11,17,40).…”