Steroid hormones may enter cells by diffusion through the plasma membrane.
However, we demonstrate here that some steroid hormones are taken up by rec
eptor-mediated endocytosis of steroid-carrier complexes. We show that 25-(O
H) vitamin D-3 in complex with its plasma carrier, the vitamin D-binding pr
otein, is filtered through the glomerulus and reabsorbed in the proximal tu
bules by the endocytic receptor megalin. Endocytosis is required to preserv
e 25-(OH) vitamin D-3 and to deliver to the cells the precursor for generat
ion of 1,25-(OH)(2) Vitamin D-3, a regulator of the calcium metabolism. Meg
alin(-/-) mice are unable to retrieve the steroid from the glomerular filtr
ate and develop vitamin D deficiency and bone disease.