25-Hydroxyvitamin D₃-1α-Hydroxylase Expression in Normal and Pathological Parathyroid Glands

Abstract

Active vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], plays a pivotal role in calcium homeostasis and bone metabolism. Circulating levels of 1,25(OH)(2)D(3) are thought to be dependent mainly on the activity of the renal cytochrome P450 enzyme 25-hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase), which is potently induced by PTH. However, 1alpha-hydroxylase activity or expression has also been reported at several extrarenal sites, at which local synthesis of 1,25(OH)(2)D(3) appears to fulfill autocrine or paracrine functions. This includes tissues such as placenta and brain that also express LRP-2/megalin, an endocytic receptor for multiple ligands, which is involved in the renal uptake of the substrate for 1alpha -hydroxylase, 25-hydroxyvitamin D(3). We have previously demonstrated LRP-2/megalin in parathyroid cells, and here we present results from RT-PCR and immunohistochemical analyses showing coincident expression of 1alpha-hydroxylase in normal and pathological parathyroid tissue. With real-time quantitative RT-PCR analysis, the expression of 1alpha-hydroxylase mRNA was higher in the majority of parathyroid adenomas and secondary hyperplastic glands but lower in parathyroid carcinomas, compared with normal parathyroid tissue. The findings imply that in addition to feedback control by circulating 1,25(OH)(2)D(3) levels, parathyroid cells may also be influenced by local 1alpha -hydroxylase activity with possible growth regulatory and differentiating effects.