Identification of a novel L-serine analog that suppresses osteoclastogenesis in vitro and bone turnover in vivo

Anton Bahtiar, Takahiro Matsumoto, Takashi Nakamura, Motofusa Akiyama, Keiichiro Yogo, Norihiro Ishida-Kitagawa, Takuya Ogawa, Tatsuo Takeya

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8 Citations (Scopus)

Abstract

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-κB 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-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.

Original languageEnglish
Pages (from-to)34157-34166
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number49
DOIs
Publication statusPublished - 4 Dec 2009

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    Bahtiar, A., Matsumoto, T., Nakamura, T., Akiyama, M., Yogo, K., Ishida-Kitagawa, N., Ogawa, T., & Takeya, T. (2009). Identification of a novel L-serine analog that suppresses osteoclastogenesis in vitro and bone turnover in vivo. Journal of Biological Chemistry, 284(49), 34157-34166. https://doi.org/10.1074/jbc.M109.058933