Novel vitamin D3 analogs, 1α, 25(OH)2D3-26, 23-lactam (DLAMs), antagonize bone resorption via suppressing RANKL expression in osteoblasts

Novel vitamin D analogs, 1α, 25-dihydroxyvitamin D3-26, 23-lactam (DLAMs) with a lactam moiety in the side chain, were synthesized and examined for their function in bone. In computer docking simulation, DLAM-1P binds to vitamin D receptor (VDR), and its lactam moiety may interfere with VDR helix-12 folding. In co-cultures of mouse bone marrow cells and osteoblasts, (23S, 25S)-DLAM-1P dose-dependently suppressed osteoclast differentiation induced by 1α, 25-dihydroxyvitamin D3 [1α, 25(OH)2D3]. Its stereoisomer (23R, 25R)-DLAM-1P did not affect the osteoclast differentiation. In osteoblasts, (23S, 25S)-DLAM-1P suppressed 1α, 25(OH)2D3-induced mRNA expression of the receptor activator of NF-κB ligand (RANKL). In an organ culture using mouse calvaria, bone-resorbing activity induced by 1α, 25(OH)2D3 was clearly suppressed by (23S, 25S)-DLAM-1P. The other analog, (23S, 25S)-DLAM-2P, showed a similar activity to (23S, 25S)-DLAM-1P. Therefore, DLAMs act on osteoblasts as an antagonist of 1α, 25(OH)2D3 to suppress RANKL-dependent osteoclast formation, suggesting them as a novel candidate for the treatment of pathological bone loss.