Identification of a novel L-serine analog that suppresses osteoclastogenesis in vitro and bone turnover in vivo.
Osteoclasts are multinucleated giant cells with bone resorbing activity. We previously reported that the expression of the transcription factor NFAT2 (NFATc1) induced by receptor activator of NF-kappaB ligand (RANKL) is essential for the formation of multinucleated cells. We subsequently identified L-Ser in the differentiation medium as necessary for the expression of NFAT2. Here we searched for serine analogs that antagonize the function of L-Ser and suppress the formation of osteoclasts in bone marrow as well as RAW264 cells. An analog thus identified, H-Ser(tBu)-OMe x HCl, appeared to suppress the production of 3-ketodihydrosphingosine by serine palmitoyltransferase, and the expression and localization of RANK, a cognate receptor of RANKL, in membrane lipid rafts was down-regulated in the analog-treated cells. The addition of lactosylceramide, however, rescued the osteoclastic formation. When administered in vivo, the analog significantly increased bone density in mice and prevented high bone turnover induced by treatment with soluble RANKL. These results demonstrate a close connection between the metabolism of L-Ser and bone remodeling and also the potential of the analog as a novel therapeutic tool for bone destruction.
Bahtiar
Anton
A
Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0101, Japan.
Matsumoto
Takahiro
T
Nakamura
Takashi
T
Akiyama
Motofusa
M
Yogo
Keiichiro
K
Ishida-Kitagawa
Norihiro
N
Ogawa
Takuya
T
Takeya
Tatsuo
T
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015519:Bone Density; D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000378:metabolism*; D004952:Esters / Q000737:chemistry; D005260:Female; D005786:Gene Expression Regulation; D015726:Giant Cells / Q000166:cytology; D066298:In Vitro Techniques; D007790:Lactosylceramides / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D012694:Serine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D051102:Serine C-Palmitoyltransferase / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
D015703:Antigens, CD; D004952:Esters; D007790:Lactosylceramides; D050778:NFATC Transcription Factors; D053245:RANK Ligand; C505688:TNFSF11 protein, human; C002882:ketodihydrosphingosine; D012694:Serine; C009744:CDw17 antigen; D051102:Serine C-Palmitoyltransferase; D013110:Sphingosine