Novel vitamin D3 analogs, 1alpha, 25(OH)2D(3)-26, 23-lactam (DLAMs), antagonize bone resorption via suppressing RANKL expression in osteoblasts.
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.
Inada
Masaki
M
Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588, Japan.
Tsukamoto
Kazuki
K
Hirata
Michiko
M
Takita
Morichika
M
Nagasawa
Kazuo
K
Miyaura
Chisato
C
D000818:Animals; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001862:Bone Resorption / Q000378:metabolism*; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D051379:Mice; D008815:Mice, Inbred Strains; D009924:Organ Culture Techniques; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects; D017510:Protein Folding; D017433:Protein Structure, Secondary / Q000187:drug effects; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000187:drug effects; D013237:Stereoisomerism
D050071:Bone Density Conservation Agents; D053245:RANK Ligand; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D002762:Cholecalciferol