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Suppression of osteoclastogenesis by N,N-dimethyl-D-erythro-sphingosine: A sphingosine kinase inhibition-independent action

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dc.contributor.authorKim, Hyung Joon-
dc.contributor.authorLee, Youngkyun-
dc.contributor.authorChang, Eun-Ju-
dc.contributor.authorKim, Hyun-Man-
dc.contributor.authorLee, Zang Hee-
dc.contributor.authorKim, Hong-Hee-
dc.contributor.authorRyu, Jiyoon-
dc.contributor.authorHong, Sam-Pyo-
dc.date.accessioned2013-01-14T07:57:42Z-
dc.date.available2013-01-14T07:57:42Z-
dc.date.issued2007-08-
dc.identifier.citationMOLECULAR PHARMACOLOGY, Vol.72, No.2, pp.418-428ko_KR
dc.identifier.issn0026-895X-
dc.identifier.urihttps://hdl.handle.net/10371/80496-
dc.description.abstractN,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 kappa B 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-kappa B, 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.ko_KR
dc.description.sponsorshipThis work was supported by the Molecular and Cellular BioDiscovery Research Program (M1–0311-00-0024) and the 21C Frontier Functional Proteomics Project Grant (FPR05C2-280) from the Korea Science and Engineering Foundation, the Ministry of Science and Technology, Korea.ko_KR
dc.description.sponsorshipThis work was supported by the Molecular and Cellular BioDiscovery Research Program (M1–0311-00-0024) and the 21C Frontier Functional Proteomics
Project Grant (FPR05C2-280) from the Korea Science and Engineering Foundation, the Ministry of Science and Technology, Korea.
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dc.language.isoenko_KR
dc.publisherAMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICSko_KR
dc.titleSuppression of osteoclastogenesis by N,N-dimethyl-D-erythro-sphingosine: A sphingosine kinase inhibition-independent actionko_KR
dc.typeArticleko_KR
dc.contributor.AlternativeAuthor김형준-
dc.contributor.AlternativeAuthor이영균-
dc.contributor.AlternativeAuthor장은주-
dc.contributor.AlternativeAuthor김현만-
dc.contributor.AlternativeAuthor이장희-
dc.contributor.AlternativeAuthor김홍희-
dc.contributor.AlternativeAuthor류지윤-
dc.contributor.AlternativeAuthor홍삼표-
dc.identifier.doi10.1124/mol.107.034173-
dc.citation.journaltitleMOLECULAR PHARMACOLOGY-
dc.description.tc12-
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