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Molecular Pharmacology

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Research ArticleArticle

Suppression of Osteoclastogenesis by N,N-Dimethyl-D-erythro-sphingosine: A Sphingosine Kinase Inhibition-Independent Action

Hyung Joon Kim, Youngkyun Lee, Eun-Ju Chang, Hyun-Man Kim, Sam-Pyo Hong, Zang Hee Lee, Jiyoon Ryu and Hong-Hee Kim
Molecular Pharmacology August 2007, 72 (2) 418-428; DOI: https://doi.org/10.1124/mol.107.034173
Hyung Joon Kim
Department of Cell and Developmental Biology and BK21 Program (H.J.K., Y.L., E.-J.C., H.-M.K., Z.H.L., J.R., H.-H.K.); and Department of Oral Pathology and DRI (S.-P.H.), School of Dentistry, Seoul National University, Seoul, Korea
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Youngkyun Lee
Department of Cell and Developmental Biology and BK21 Program (H.J.K., Y.L., E.-J.C., H.-M.K., Z.H.L., J.R., H.-H.K.); and Department of Oral Pathology and DRI (S.-P.H.), School of Dentistry, Seoul National University, Seoul, Korea
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Eun-Ju Chang
Department of Cell and Developmental Biology and BK21 Program (H.J.K., Y.L., E.-J.C., H.-M.K., Z.H.L., J.R., H.-H.K.); and Department of Oral Pathology and DRI (S.-P.H.), School of Dentistry, Seoul National University, Seoul, Korea
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Hyun-Man Kim
Department of Cell and Developmental Biology and BK21 Program (H.J.K., Y.L., E.-J.C., H.-M.K., Z.H.L., J.R., H.-H.K.); and Department of Oral Pathology and DRI (S.-P.H.), School of Dentistry, Seoul National University, Seoul, Korea
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Sam-Pyo Hong
Department of Cell and Developmental Biology and BK21 Program (H.J.K., Y.L., E.-J.C., H.-M.K., Z.H.L., J.R., H.-H.K.); and Department of Oral Pathology and DRI (S.-P.H.), School of Dentistry, Seoul National University, Seoul, Korea
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Zang Hee Lee
Department of Cell and Developmental Biology and BK21 Program (H.J.K., Y.L., E.-J.C., H.-M.K., Z.H.L., J.R., H.-H.K.); and Department of Oral Pathology and DRI (S.-P.H.), School of Dentistry, Seoul National University, Seoul, Korea
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Jiyoon Ryu
Department of Cell and Developmental Biology and BK21 Program (H.J.K., Y.L., E.-J.C., H.-M.K., Z.H.L., J.R., H.-H.K.); and Department of Oral Pathology and DRI (S.-P.H.), School of Dentistry, Seoul National University, Seoul, Korea
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Hong-Hee Kim
Department of Cell and Developmental Biology and BK21 Program (H.J.K., Y.L., E.-J.C., H.-M.K., Z.H.L., J.R., H.-H.K.); and Department of Oral Pathology and DRI (S.-P.H.), School of Dentistry, Seoul National University, Seoul, Korea
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Abstract

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.

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Molecular Pharmacology: 72 (2)
Molecular Pharmacology
Vol. 72, Issue 2
1 Aug 2007
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Research ArticleArticle

Suppression of Osteoclastogenesis by N,N-Dimethyl-D-erythro-sphingosine: A Sphingosine Kinase Inhibition-Independent Action

Hyung Joon Kim, Youngkyun Lee, Eun-Ju Chang, Hyun-Man Kim, Sam-Pyo Hong, Zang Hee Lee, Jiyoon Ryu and Hong-Hee Kim
Molecular Pharmacology August 1, 2007, 72 (2) 418-428; DOI: https://doi.org/10.1124/mol.107.034173

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Research ArticleArticle

Suppression of Osteoclastogenesis by N,N-Dimethyl-D-erythro-sphingosine: A Sphingosine Kinase Inhibition-Independent Action

Hyung Joon Kim, Youngkyun Lee, Eun-Ju Chang, Hyun-Man Kim, Sam-Pyo Hong, Zang Hee Lee, Jiyoon Ryu and Hong-Hee Kim
Molecular Pharmacology August 1, 2007, 72 (2) 418-428; DOI: https://doi.org/10.1124/mol.107.034173
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