Bone is a dynamic tissue, constantly undergoing growth, remodelling and degradation. Central to these processes are the osteoclasts, bone-resorbing multinuclear giant cells that differentiate from mononuclear macrophage/monocyte-lineage haematopoietic precursors. Normally bone resorption is balanced by the activity of bone-forming osteoblasts, but in bone-destructive disorders such as osteoporosis, osteoclast activity outpaces osteoblast activity. Now using a mouse model of hormone-deprivation osteoporosis, the blood-born lipid mediator sphingosine-1-phosphate is identified as a key mediator of bone demineralization. It controls the migratory behaviour of osteoclast precursors, thereby regulating bone homeostasis. As a pivotal control point in osteoclastogenesis, sphingosine-1-phosphate may have potential, as a therapeutic target in bone-resorptive disorders. Osteoclasts resorb bone and their precursor cells express sphingosine-1-phosphate (S1P) receptors. Too much S1P, and too many osteoclast precursors move into the blood; too little S1P results in increased attachment to bone and osteoporosis. Furthermore, S1P receptor stimulation in live mice diminishes bone loss in a mouse model of postmenopausal osteoporosis. 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-κB-ligand (RANKL, also known as TNFSF11) and TNF-α, both of which have been well documented to contribute to osteoclast terminal differentiation2,3. 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 blood4,5, 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.

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