Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling

EMBO J. 2006 Dec 13;25(24):5840-51. doi: 10.1038/sj.emboj.7601430. Epub 2006 Nov 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects*
  • Cell Survival / drug effects
  • Chemotaxis / drug effects
  • Coculture Techniques
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • HeLa Cells
  • Humans
  • Lymphocyte Activation / drug effects
  • Lysophospholipids / pharmacology*
  • Mice
  • NFATC Transcription Factors / metabolism
  • Osteoblasts / cytology*
  • Osteoblasts / drug effects*
  • Osteoblasts / metabolism
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects*
  • Osteogenesis / drug effects
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism
  • RANK Ligand / genetics
  • RANK Ligand / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Lysophospholipids
  • NFATC Transcription Factors
  • Proto-Oncogene Proteins c-fos
  • RANK Ligand
  • RNA, Messenger
  • sphingosine 1-phosphate
  • Cyclooxygenase 2
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Dinoprostone
  • Sphingosine