title: Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling.
abstract: Sphingosine 1-phosphate (S1P), produced by sphingosine kinase (SPHK), acts both by intracellular and extracellular modes. We evaluated the role of SPHK1 and S1P in osteoclastogenesis using bone marrow-derived macrophage (BMM) single and BMM/osteoblast coculture systems. In BMM single cultures, the osteoclastogenic factor receptor activator of NF-kappaB ligand (RANKL) upregulated SPHK1 and increased S1P production and secretion. SPHK1 siRNA enhanced and SPHK1 overexpression attenuated osteoclastogenesis via modulation of p38 and ERK activities, and NFATc1 and c-Fos levels. Extracellular S1P had no effect in these cultures. These data suggest that intracellular S1P produced in response to RANKL forms a negative feedback loop in BMM single cultures. In contrast, S1P addition to BMM/osteoblast cocultures greatly increased osteoclastogenesis by increasing RANKL in osteoblasts via cyclooxygenase-2 and PGE(2) regulation. S1P also stimulated osteoblast migration and survival. The RANKL elevation and chemotactic effects were also observed with T cells. These results indicate that secreted S1P attracts and acts on osteoblasts and T cells to augment osteoclastogenesis. Taken together, S1P plays an important role in osteoclastogenesis regulation and in communication between osteoclasts and osteoblasts or T cells.
authors.affiliation: Department of Cell and Developmental Biology, BK21 Program, DRI, Seoul National University, 28 Yeongon-Dong, Chongno-Gu, Seoul 110-749, Korea.
authors.forename: Jiyoon
authors.initials: J
authors.lastname: Ryu
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Chang
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Banno
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008246:Lysophospholipids / Q000494:pharmacology*; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D051546:Cyclooxygenase 2; D015232:Dinoprostone; D048049:Extracellular Signal-Regulated MAP Kinases; D008246:Lysophospholipids; D050778:NFATC Transcription Factors; D017853:Phosphotransferases (Alcohol Group Acceptor); D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D012333:RNA, Messenger; D013110:Sphingosine; D048051:p38 Mitogen-Activated Protein Kinases; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate