Inada Masaki, Tsukamoto Kazuki, Hirata Michiko, Takita Morichika, Nagasawa Kazuo, Miyaura Chisato
Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan.
Biochem Biophys Res Commun. 2008 Aug 1;372(3):434-9. doi: 10.1016/j.bbrc.2008.05.041. Epub 2008 May 19.
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.
新型维生素D类似物，即侧链带有内酰胺部分的1α,25 - 二羟基维生素D(3)-26,23 - 内酰胺（DLAMs），已被合成并对其在骨骼中的功能进行了研究。在计算机对接模拟中，DLAM - 1P与维生素D受体（VDR）结合，其内酰胺部分可能会干扰VDR螺旋-12的折叠。在小鼠骨髓细胞和成骨细胞的共培养中，(23S,25S)-DLAM - 1P呈剂量依赖性地抑制了由1α,25 - 二羟基维生素D(3)[1α,25(OH)₂D₃]诱导的破骨细胞分化。其立体异构体(23R,25R)-DLAM - 1P对破骨细胞分化没有影响。在成骨细胞中，(23S,25S)-DLAM - 1P抑制了1α,25(OH)₂D₃诱导的核因子κB受体激活剂配体（RANKL）的mRNA表达。在使用小鼠颅骨的器官培养中，(23S,25S)-DLAM - 1P明显抑制了由1α,25(OH)₂D₃诱导的骨吸收活性。另一种类似物(23S,25S)-DLAM - 2P表现出与(23S,25S)-DLAM - 1P相似的活性。因此，DLAMs作为1α,25(OH)₂D₃的拮抗剂作用于成骨细胞，以抑制RANKL依赖性破骨细胞的形成，表明它们是治疗病理性骨质流失的新型候选药物。
