23(S)25(R)-1,25-Dihydroxyvitamin D₃-lactone, a naturally occurring metabolite of 1,25-dihydroxyvitamin D₃, inhibits osteoclast-like cell formation in human bone marrow cultures

Abstract:

We have used a human bone marrow culture system that forms multinucleated cells (MNCs), 50% of which express the osteoclast phenotype, to examine the 23(S)25(R)-1,25-dihydroxyvitamin D₃-26,23-lactone (1,25-D₃-lactone) on osteoclast-like cell formation. The 1,25-D₃-lactone is a vitamin D₃ metabolite that has recently been detected in human serum under physiological conditions at concentrations of approximately 131 pg/ml (3 × 10⁻¹⁰ M) and can inhibit bone resorption induced by 1,25-dihydroxyvitamin D₃ (1,25-D₃) in vivo and in vitro. We examined the effects of the 1,25-D₃-lactone on the formation of MNC that cross-reacted with 23C6 monoclonal antibody (23C6-positive MNC), which preferentially binds to osteoclasts. All metabolites of 1,25-D₃ except the 1,25-D3-lactone increased both total and 23C6-positive MNC formation in a dose-dependent manner. In contrast, the 1,25-D₃-lactone inhibited both total and 23C6-positive MNC formation, whether the cultures were treated with 1,25-D₃, parathyroid hormone, or interleukin-1β, all potent stimulators of MNC formation. This inhibitory action of 1,25-D₃-lactone on MNC formation was very similar to the inhibitory effects of calcitonin. These data suggest that (1) 1,25-D₃-lactone is a potent natural inhibitor of formation of cells with the osteoclast phenotype at physiological concentrations and (2) the inhibition of these cells by 1,25-D₃-lactone may not result solely from its competitive binding to the 1,25-D₃ receptor.