Sphingosine-1-phosphate-mediated osteoclast precursor monocyte migration is a critical point of control in antibone-resorptive action of active vitamin D

Abstract

The migration and positioning of osteoclast precursor monocytes are controlled by the blood-enriched lipid mediator sphingosine-1-phosphate (S1P) and have recently been shown to be critical points of control in osteoclastogenesis and bone homeostasis. Here, we show that calcitriol, which is the hormonally active form of vitamin D, and its therapeutically used analog, eldecalcitol, inhibit bone resorption by modulating this mechanism. Vitamin D analogs have been used clinically for treating osteoporosis, although the mode of its pharmacologic action remains to be fully elucidated. In this study, we found that active vitamin D reduced the expression of S1PR2, a chemorepulsive receptor for blood S1P, on circulating osteoclast precursor monocytes both in vitro and in vivo. Calcitriol-or eldecalcitol-treated monocytoid RAW264.7 cells, which display osteoclast precursor-like properties, migrated readily to S1P. Concordantly, the mobility of circulating CX 3 CR1 + osteoclast precursor monocytes was significantly increased on systemic administration of active vitamin D. These results show a mechanism for active vitamin D in controlling the migratory behavior of circulating osteoclast precursors, and this action should be conducive to limiting osteoclastic bone resorption in vivo.B one is a highly dynamic organ, and it is continuously remodeled cooperatively by bone-resorbing osteoclasts and bone-replenishing osteoblasts (1). Osteoclasts, which have bone-resorbing capacity, are a unique cell type differentiated from monocyte/ macrophage lineage hematopoietic precursor cells termed osteoclast precursors. Previous studies have identified key molecular signals, such as mediated by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL), that regulate osteoclastic differentiation and function (2, 3). Unlike osteoblasts, which are of mesenchymal origin and essentially reside in bone tissues, osteoclasts and their precursor monocytes are highly dynamic. Their migratory mechanisms in systemic circulation and homing into bone spaces have recently emerged as critical points of control for osteoclastogenesis and thus, bone homeostasis. We have recently used intravital two-photon microscopy to visualize the bone tissues of live mice and found that sphingosine-1-phosphate (S1P), a lysophospholipid mediator enriched in blood, plays a vital role in regulating the migration and positioning of osteoclast precursors on the bone surface (4, 5).Osteoclast precursor monocytes express S1PR1 (formerly designated as S1P 1 or Edg-1), a cognate receptor for S1P, and can use this receptor to migrate from bone tissues to blood that contains S1P. The deletion of S1PR1 in monocytoid cells leads to an accumulation of osteoclast precursors and a resultant increase in bone resorption, which suggests that the S1P-S1PR1 interaction is essential for the recirculation of osteoclast precursors from bone to blood (4). The expression of S1PR1 was suppressed on stimulation with RANKL, representing a reasonable mechanism wher...

Transcriptional activation of the wild-type and mutant vitamin D receptors by vitamin D3 analogs

“…The binding affinity of eldecalcitol to the VDR is about 50% of that of calcitriol (Hatakeyama et al 2010), and the molecular mechanism underlying its superior therapeutic effect for treating osteoporosis is currently unknown. One characteristic feature of eldecalcitol is its high binding affinity for vitamin D-binding protein in serum (Kikuta et al 2013), suggesting that free eldecalcitol can be present in blood without binding to the VDR. These observations suggest that although VD 3 analogs act through the VDR, other factors may be involved in their transcriptional activities (Carlberg 2014).…”

Visualized macrophage dynamics and significance of S100A8 in obese fat

“…Sequential images were taken every 30 s for 1 h. Image stacks were collected at a 5-μm vertical step size. To quantify leukocyte dynamics, raw imaging data were processed as follows: EGFP-positive cells in sections were tracked, and mobility was calculated as the mean tracking velocity and mean tracking length by using IMARIS 3D and 4D real-time image processing and analysis software (Bitplane) (32,33).…”

Vitamin D analogs and bone: preclinical and clinical studies with eldecalcitol

“…Ishii et al 15 demonstrated that RANKL stimulation suppresses the expression of S1PR1 and enhances osteoclast formation, whereas calcitriol and eldecalcitol suppress the expression of S1PR2 to enhance migration of osteoclast precursors from bone to blood circulation and thus suppress osteoclast formation ( Figure 1). 16 Although these results cannot explain the stronger suppressive effect of eldecalcitol on bone resorption, the much higher affinity of eldecalcitol for serum vitamin D-binding protein than alfacalcidol may yield a higher concentration of eldecalcitol in the bone marrow and give it a superior suppressive effect on bone resorption.…”