1. Lymphocyte Biology Section, Laboratory of Immunology
2. Program in Systems Immunology and Infectious Disease Modeling, National Institute of Allergy and Infectious Diseases, and,
3. Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892, USA
4. Laboratory of Biological Imaging, WPI-Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
5. Department of Clinical Research, National Osaka Minami Medical Center, Osaka 586-8521, Japan
6. Institut de Recherches Cliniques de Montréal, Quebec H2W 1R7, Canada

Correspondence to: Ronald N. Germain^1,2 Correspondence and requests for materials should be addressed to R.N.G. (Email: rgermain@niaid.nih.gov).

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 osteoporosis¹. A major focus of research in the field has been on gene regulation by osteoclastogenic cytokines such as receptor activator of NF-B-ligand (RANKL, also known as TNFSF11) and TNF-, both of which have been well documented to contribute to osteoclast terminal differentiation^{2, 3}. 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^{4, 5}, 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 S1P₁ receptors and exhibit positive chemotaxis along an S1P gradient in vitro. Intravital two-photon imaging of bone tissues showed that a potent S1P₁ agonist, SEW2871, stimulated motility of osteoclast precursor-containing monocytoid populations in vivo. Osteoclast/monocyte (CD11b, also known as ITGAM) lineage-specific conditional S1P₁ knockout mice showed osteoporotic changes due to increased osteoclast attachment to the bone surface. Furthermore, treatment with the S1P₁ 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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