Novel vitamin D3 analogs, 1alpha, 25(OH)2D(3)-26, 23-lactam (DLAMs), antagonize bone resorption via suppressing RANKL expression in osteoblasts

Masaki Inada, Kazuki Tsukamoto, Michiko Hirata, Morichika Takita, Kazuo Nagasawa, Chisato Miyaura
Biochemical and Biophysical Research Communications 2008 August 1, 372 (3): 434-9
Novel vitamin D analogs, 1alpha, 25-dihydroxyvitamin D(3)-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 1alpha, 25-dihydroxyvitamin D(3) [1alpha, 25(OH)(2)D(3)]. Its stereoisomer (23R,25R)-DLAM-1P did not affect the osteoclast differentiation. In osteoblasts, (23S,25S)-DLAM-1P suppressed 1alpha, 25(OH)(2)D(3)-induced mRNA expression of the receptor activator of NF-kappaB ligand (RANKL). In an organ culture using mouse calvaria, bone-resorbing activity induced by 1alpha, 25(OH)(2)D(3) 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 1alpha, 25(OH)(2)D(3) to suppress RANKL-dependent osteoclast formation, suggesting them as a novel candidate for the treatment of pathological bone loss.

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