Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling.
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.
Mesh Terms:
Animals, Cell Differentiation, Cell Survival, Chemotaxis, Coculture Techniques, Cyclooxygenase 2, Dinoprostone, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Enzymologic, HeLa Cells, Humans, Lymphocyte Activation, Lysophospholipids, Mice, NFATC Transcription Factors, Osteoblasts, Osteoclasts, Osteogenesis, Phosphotransferases (Alcohol Group Acceptor), Proto-Oncogene Proteins c-fos, RANK Ligand, RNA, Messenger, Sphingosine, T-Lymphocytes, p38 Mitogen-Activated Protein Kinases
Animals, Cell Differentiation, Cell Survival, Chemotaxis, Coculture Techniques, Cyclooxygenase 2, Dinoprostone, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Enzymologic, HeLa Cells, Humans, Lymphocyte Activation, Lysophospholipids, Mice, NFATC Transcription Factors, Osteoblasts, Osteoclasts, Osteogenesis, Phosphotransferases (Alcohol Group Acceptor), Proto-Oncogene Proteins c-fos, RANK Ligand, RNA, Messenger, Sphingosine, T-Lymphocytes, p38 Mitogen-Activated Protein Kinases
EMBO J.
Date: Dec. 13, 2006
PubMed ID: 17124500
View in: Pubmed Google Scholar
Download Curated Data For This Publication
151415
Switch View:
- Interactions 2