role of 1,25-(OH)2D3 in regulating parathyroid gland function

Parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) (the biologically active metabolite of vitamin D3) are the two major hormones responsible for the maintenance of calcium homeostasis. In carrying out their biologic actions, the two hormones interact with the kidney, bone, and gastrointestinal tract (1). Parathyroid hormone enhances calcium reabsorption in the distal renal tubule and decreases phosphate absorption by the proximal tubule, and 1,25-(OH)2D3 enhances calcium absorption by the intestine by a mechanism that is still not completely understood. In concert, a peptide hormone (PTH) acts with a 9,10-secosterol (1,25-(OH)2D3) to mobilize calcium from bone into the extracellular fluid. PTH also enhances the production of 1,25-(OH)2D3 by the kidney through activation of the 1 α-hydroxylase enzyme which is responsible for converting 25-(OH)D3 to 1,25-(OH)2D3, the final activating step for vitamin D3. What has been less clear are the effects of 1,25-(OH)2D3 on parathyroid gland function and specifically on PTH synthesis and secretion. Recent studies (2–4) have provided considerable clarification of this issue and emphasized a key role for 1,25-(OH)2D3 in regulating parathyroid gland function. Nuclear receptors for 1,25-(OH)2D3, similar to receptors for steroid hormones, have been identified in target tissues for the hormone, namely, the intestine and bone (5, 6). Similar high affinity receptors have been demonstrated in parathyroid cells from the chicken and other species (7–9). Following the administration of [3H]1,25-(OH)2D3 to rats and chicks, there is marked accumulation of the active metabolite in the nuclei of parathyroid cells. The 1,25-(OH)2D3 receptor has now been cloned and sequenced; it contains DNA-and ligand-binding domains analogous to steroid receptors that affect gene expression (10). There has previously been confusion about the potential role of 1,25-(OH)2D3 in parathyroid gland function, with reports in the literature suggesting that the active metabolite suppresses, stimulates, or has no effect on PTH release (11–15).