PT - JOURNAL ARTICLE AU - Hyung Joon Kim AU - Youngkyun Lee AU - Eun-Ju Chang AU - Hyun-Man Kim AU - Sam-Pyo Hong AU - Zang Hee Lee AU - Jiyoon Ryu AU - Hong-Hee Kim TI - Suppression of Osteoclastogenesis by <em>N</em>,<em>N</em>-Dimethyl-D-<em>erythro</em>-sphingosine: A Sphingosine Kinase Inhibition-Independent Action AID - 10.1124/mol.107.034173 DP - 2007 Aug 01 TA - Molecular Pharmacology PG - 418--428 VI - 72 IP - 2 4099 - http://molpharm.aspetjournals.org/content/72/2/418.short 4100 - http://molpharm.aspetjournals.org/content/72/2/418.full SO - Mol Pharmacol2007 Aug 01; 72 AB - N,N-Dimethyl-d-erythro-sphingosine (DMS) competitively inhibits sphingosine kinase (SPHK) and has been widely used to assess the role of SPHK during cellular events, including motility, proliferation, and differentiation. In the present study, the effect of DMS on the differentiation of bone marrow macrophages (BMMs) to osteoclasts was investigated. When the osteoclast precursor cells were treated with DMS, the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis was completely blocked. We were surprised to find, however, that knock-down of SPHK by small interfering RNA (siRNA) in BMMs did not reduce osteoclastogenesis. Furthermore, both overexpression of SPHK and exogenous addition of sphingosine-1-phosphate, the product of SPHK activity, failed to overcome the antiosteoclastogenic effect of DMS. These results suggest that DMS inhibited osteoclastogenesis independently of SPHK. Subsequent characterization of the DMS-mediated suppression of osteoclastogenesis revealed that DMS did not affect RANKL-induced activation of JNK, p38, NF-κB, and Ca2+ oscillation. On the other hand, DMS strongly inhibited two separate signaling pathways, the RANKL-induced activation of ERK and Akt, which eventually converged on the transcription factors c-Fos and NFATc1. There was significant increase in the osteoclast formation in the presence of DMS when BMMs were overexpressed with c-Fos, suggesting that c-Fos was a critical downstream target of DMS for the inhibition of osteoclastogenesis. Taken together, our data demonstrate that DMS has an antiosteoclastogenic function independently of its SPHK inhibitory activity. Considering previously reported anticancer properties of DMS, our study may also propose that DMS is an ideal drug candidate for bone metastases, for which osteoclastic bone-resorption is crucial.