RT Journal Article SR Electronic T1 Suppression of Osteoclastogenesis by N,N-Dimethyl-D-erythro-sphingosine: A Sphingosine Kinase Inhibition-Independent Action JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 418 OP 428 DO 10.1124/mol.107.034173 VO 72 IS 2 A1 Hyung Joon Kim A1 Youngkyun Lee A1 Eun-Ju Chang A1 Hyun-Man Kim A1 Sam-Pyo Hong A1 Zang Hee Lee A1 Jiyoon Ryu A1 Hong-Hee Kim YR 2007 UL http://molpharm.aspetjournals.org/content/72/2/418.abstract 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.