Electrical responses to 1alpha,25(OH)2-Vitamin D3 and their physiological significance in osteoblasts.

Osteoblasts are a main target for the steroid 1alpha,25(OH)2-Vitamin D3 (1,25D3), where a major outcome is the modulation of the bone remodeling process. 1,25D3 deficiency leads to clinical disorders such as osteomalacia and osteoporosis, characterized by a state of insufficiently calcified tissue and bone loss, respectively. In the osteoblast nucleus, 1,25D3 modulates gene transcription for the synthesis of bone matrix proteins via the Vitamin D receptor (VDR). At the plasma membrane level, 1,25D3 potentiates ion channel functions, activates signal transduction pathways, and increases cytoplasmic calcium concentrations. So far, no clear physiological significance has been attributed to membrane-initiated 1,25D3 actions in single cells. To investigate if (a) 1,25D3 is a modulatory agent of secretion in osteoblasts and (b) the classical VDR is involved in rapid electrical events in the cell membrane, we studied hormone effects on ion channel activities in relation to exocytosis in osteoblasts isolated from VDR knockout (KO) and wild-type (WT) mice. This paper is a retrospect of the electrophysiological studies done in our laboratory to date. We found that 1,25D3-promoted ion channel responses are coupled to secretion in calvarial osteoblasts, and develop only in the presence of a functional nuclear steroid VDR. This 1,25D3-regulated exocytosis in osteoblasts, which takes place within minutes of hormone application, seems to be the natural complement of genomic actions that evolve at a longer time scale. The absence of both 1,25D3 membrane and nuclear effects in VDR KO osteoblasts may explain bone abnormalities typically found in VDR KO mice.