Autocrine Regulation of Parathyroid Cell Secretion and Proliferation

Sparse information is available on the expression and actions of growth factors in the parathyroid parenchyma. Insulin-like growth factor I and its receptor seem to be expressed by parathyroid tissue, and EGF may play a role in cellular proliferation.100 Fibroblastic growth factors (FGFs) are mitogenic peptides synthesized by parathyroid epithelial and endothelial cells. Production of acidic FGF increases under hypocalcemic conditions, when high-affinity receptors for this peptide seem to translocate to the parathyroid cell surface.101 Because the peptide lacks a classic consensus signal peptide sequence, however, meager secretion from cells is characteristic and perhaps involves mechanisms other than the conventional endoplasmic reticulum-Golgi complex.102

It has long been known that human parathyroid tissue secretes chromogranin A, an equivalent to secretory protein l.103 This acidic protein is costored in the secretory granules and cosecreted with PTH in response to alterations in the extracellular calcium concentration,104 105 whereas calcitriol exhibits opposite effects on PTH and chromogranin A gene transcription.106 Pancreastatin and other cleavage products of the chromogranin A peptide precursor have been found to inhibit PTH release in various species.104'107 108 The possibility of intraglandular autocrine or paracrine control of PTH release exists. Theoretically, such a mechanism could participate in sharpening or elongating the responses of the parathyroid gland to secretory agonists or antagonists. The relevance of this phenomenon remains to be elucidated, however, because human pancreastatin 1-52 and 34-52 fail to influence human PTH release.109 Moreover, the chief and oxyphil cells of human parathyroid glands express PTH-related protein (PTHrP) on the surface membrane, which may have paracrine or autocrine roles in the adult parathyroid.110111

Endothelin is a potent smooth muscle cell constrictor, which exists in different isoforms and binds to specific receptors. Endothelin is synthesized by parathyroid cells and perhaps parathyroid endothelial cells, and endothelin receptors are expressed by the parathyroid parenchyma.112113 Endothelin has been found to inhibit PTH release, and endothelin mRNA production of the parathyroid is sensitive to the extracellular calcium concentration. Moreover, endothelin is unique because it seems to affect PTH release by interfering with parathyroid Ca2+j (unpublished data). These circumstances indicate that this protein may be an autocrine or a paracrine regulator of PTH release, or both.

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