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Cited by 515Bone Metabolism and DiseasesSphingolipid Metabolism and SignalingBone health and osteoporosis research

Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis

Open access
Ishii, Masaru, Egen, Jackson G., Klauschen, Frederick, Meier-Schellersheim, Martin, Saeki, Yukihiko, Vacher, Jean, Proia, Richard L., Germain, Ronald N.·2009·Nature
DOI 10.1038/nature07713PMC PMC2785034
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Abstract

Osteoclasts are the only somatic cells with bone-resorbing capacity and, as such, they have a critical role not only in normal bone homeostasis (called 'bone remodelling') but also in the pathogenesis of bone destructive disorders such as rheumatoid arthritis and osteoporosis. A major focus of research in the field has been on gene regulation by osteoclastogenic cytokines such as receptor activator of NF-kappaB-ligand (RANKL, also known as TNFSF11) and TNF-alpha, both of which have been well documented to contribute to osteoclast terminal differentiation. A crucial process that has been less well studied is the trafficking of osteoclast precursors to and from the bone surface, where they undergo cell fusion to form the fully differentiated multinucleated cells that mediate bone resorption. Here we report that sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood, induces chemotaxis and regulates the migration of osteoclast precursors not only in culture but also in vivo, contributing to the dynamic control of bone mineral homeostasis. Cells with the properties of osteoclast precursors express functional S1P(1) receptors and exhibit positive chemotaxis along an S1P gradient in vitro. Intravital two-photon imaging of bone tissues showed that a potent S1P(1) agonist, SEW2871, stimulated motility of osteoclast precursor-containing monocytoid populations in vivo. Osteoclast/monocyte (CD11b, also known as ITGAM) lineage-specific conditional S1P(1) knockout mice showed osteoporotic changes due to increased osteoclast attachment to the bone surface. Furthermore, treatment with the S1P(1) agonist FTY720 relieved ovariectomy-induced osteoporosis in mice by reducing the number of mature osteoclasts attached to the bone surface. Together, these data provide evidence that S1P controls the migratory behaviour of osteoclast precursors, dynamically regulating bone mineral homeostasis, and identifies a critical control point in osteoclastogenesis that may have potential as a therapeutic target.

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  • Bone marrow osteoclast hematopoietic stem cells expressing S1PR2 enter the circulation by binding S1P, a chemotactic lysophospholipid normally present in high concentrations in blood.

    “Bone marrow osteoclast hematopoietic stem cells (HSCs) expressing type-2 receptor for sphingosine-1-phosphate (S1PR2) enter the circulation by binding sphingosine-1-phosphate (S1P), a chemotactic lysophospholipid normally present in high concentrations in blood [15,16].”

    From Osteoclasts and Microgravity (2020) · cites this paper as [15]

    The paper’s Abstract supports S1P-driven recirculation of osteoclast precursors toward blood, where S1P levels are high. But it identifies the migrating cells as monocyte-lineage precursors, not hematopoietic stem cells, and attributes the demonstrated recirculation mechanism to S1P1 rather than S1PR2; it reports S1P2 mRNA expression without establishing that mechanism for S1P2. No page number is available in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • HSCs may be recycled to the bone marrow by binding S1P to S1PR1 or stay at bone surfaces where they evolve into mature osteoclasts by binding M-CSF and RANKL produced primarily by osteoblasts, osteocytes, and stromal cells.

    “HSCs may then be recycled to the bone marrow by binding S1P to type-1 receptors (S1PR1) or stay at bone surfaces where they evolve into mature osteoclasts by binding M-CSF and RANKL produced primarily by osteoblasts, osteocytes, and stromal cells [15,16] (Figure 2).”

    From Osteoclasts and Microgravity (2020) · cites this paper as [15]

    The paper’s discussion of precursor recirculation (indexed as Abstract; page unavailable) supports S1P–S1P1 signaling and RANKL-associated maturation at the bone surface. But it describes monocyte-lineage osteoclast precursors moving from bone tissue into the blood, not HSCs returning to bone marrow. The Cell culture methods identify M-CSF-dependent precursors, but the paper does not establish that M-CSF and RANKL are produced primarily by the three cell types named in the claim. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 29

  1. [1]Teitelbaum SL Bone resorption by osteoclasts Science 289 1504 1508 2000 10968780
  2. [2]Teitelbaum SL Ross FP Genetic regulation of osteoclast development and function Nat Rev Genet 4 638 649 2003 12897775
  3. [3]Karsenty G Wagner EF Reaching a genetic and molecular understanding of skeletal development Dev Cell 2 389 406 2002 11970890
  4. [4]Rosen H Goetzl EJ Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network Nat Rev Immunol 5 560 570 2005 15999095
  5. [5]Cyster JG Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs Annu Rev Immunol 23 127 159 2005 15771568
  6. [6]Bokoch GM Katada T Northup JK Ui M Gilman AG Purification and properties of the inhibitory guanine nucleotide-binding regulatory component of adenylate cyclase J Biol Chem 259 3560 3567 1984 6323429
  7. [7]Akbar H Cancelas J Williams DA Zheng J Zheng Y Rational design and applications of a Rac GTPase-specific small molecule inhibitor Methods Enzymol 406 554 565 2006 16472687
  8. [8]Spiegel S English D Milstien S Sphingosine 1-phosphate signaling: providing cells with a sense of direction Trends Cell Biol 12 236 242 2002 12062172
  9. [9]Takuwa Y Subtype-specific differential regulation of Rho family G proteins and cell migration by the Edg family sphingosine-1-phosphate receptors Biochim Biophys Acta 1582 112 120 2002 12069818
  10. [10]Mazo IB Hematopoietic progenitor cell rolling in bone marrow microvessels: parallel contributions by endothelial selectins and vascular cell adhesion molecule 1 J Exp Med 188 465 474 1998 9687524 PMC2212463
  11. [11]Mazo IB Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells Immunity 22 259 270 2005 15723813
  12. [12]Jung S Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion Mol Cell Biol 20 4106 4114 2000 10805752 PMC85780
  13. [13]Niess JH CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance Science 307 254 258 2005 15653504
  14. [15]Sanna MG Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate J Biol Chem 279 13839 13848 2004 14732717
  15. [16]Wei SH Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses Nat Immunol 6 1228 1235 2005 16273098
  16. [17]Liu Y Edg-1, the G protein-coupled receptor for sphingosine-1-phoshate, is essential for vascular maturation J Clin Invest 106 951 961 2000 11032855 PMC314347
  17. [18]Allende ML G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation Blood 102 3665 3667 2003 12869509
  18. [19]Ferron M Vacher J Targeted expression of Cre recombinase in macrophages and osteoclasts in transgenic mice Genesis 41 138 145 2005 15754380
  19. [20]Filgueira L Fluorescence-based staining for tartrate-resistant acidic phosphatase (TRAP) in osteoclasts combined with other fluorescent dyes and protocols J Histochem Cytochem 52 411 414 2004 14966208
  20. [21]Stoller P Reiser KM Celliers PM Rubenchik AM Polarization-modulated second harmonic generation in collagen Biophys J 82 3330 3342 2002 12023255 PMC1302120
  21. [22]Yu X Huang Y Collin-Osdoby P Osdoby P Stromal cell-derived factor-1 (SDF-1) recruits osteoclast precursors by inducing chemotaxis, matrix metalloprotease-9 (MMP-9) activity, and collagen transmigration J Bone Miner Res 18 1404 1418 2003 12929930
  22. [23]Katayama Y Battista M Kao WM Hidalgo A Peired AJ Thomas SA Frenette PS Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow Cell 124 407 421 2006 16439213
  23. [24]Matloubian M Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1 Nature 427 355 360 2004 14737169
  24. [25]Cyster JG Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs Annu Rev Immunol 23 127 159 2005 15771568
  25. [26]Kappos L Oral fingolimod (FTY720) for relapsing multiple sclerosis N Engl J Med 355 1124 1140 2006 16971719
  26. [27]Tedesco-Silva H FTY720 versus mycophenolate mofetil in de novo renal transplantation: six-month results of a double-blind study Transplantation 84 885 892 2007 17984842
  27. [28]Kobayashi K Tumor necrosis factor α stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction J Exp Med 191 275 286 2000 10637272 PMC2195746
  28. [29]Ishii M RANKL-induced expression of tetraspanin CD9 in lipid raft membrane microdomain is essential for cell fusion during osteoclastogenesis J Bone Miner Res 21 965 976 2006 16753027
  29. [30]Okamoto H Inhibitory regulation of Rac activation, membrane ruffling, and cell migration by the G protein-coupled sphingosine-1-phosphate receptor EDG5 but not EDG1 or EDG3 Mol Cell Biol 20 9247 9261 2000 11094076 PMC102182

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Authors
Ishii, M., Egen, J. G., Klauschen, F., Meier-Schellersheim, M., Saeki, Y., Vacher, J., Proia, R. L., & Germain, R. N.
Affiliations
  • National Institutes of Health (US)
  • National Institute of Allergy and Infectious Diseases (US)
  • Osaka Minami Medical Center (JP)
  • Montreal Clinical Research Institute (CA)
Corresponding author
Germain, Ronald N.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2009-02-08
Volume
458
Issue
7237
Pages
524-528
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature07713
PMC
PMC2785034
OpenAlex
W2051011991
Cited by
515
References
1
Citations by year
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FWCI
16.66
Type
journal article
Language
en
Update notices
erratum (2010-06-17)
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • U.S. Department of Health and Human Services
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (ZIAAI000545)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords
sphingosine-1-phosphate, osteoclast precursors, bone homeostasis, osteoporosis, postmenopausal osteoporosis, osteoclastogenesis, chemotaxis, cell migration, bone resorption, S1P receptors, bone demineralization, lipid mediators, bone remodeling, RANKL
MeSH terms
Fingolimod Hydrochloride, Animals, Bone and Bones, Bone Resorption, Cell Line, Chemotaxis, Female, Homeostasis, Lysophospholipids, Mice, Inbred C57BL, Monocytes, Osteoclasts, Osteoporosis, Ovariectomy, Propylene Glycols, Sphingosine, Bone Density, Cell Lineage, Receptors, Lysosphingolipid, Mice

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