The Role of 1,25-(OH) 2 D 3 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).