Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo.
Sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood, controls the dynamic migration of osteoclast (OC) precursors (OPs) between the blood and bone, in part via the S1P receptor 1 (S1PR1) which directs positive chemotaxis toward S1P. We show that OPs also express S1PR2, an S1P receptor which mediates negative chemotaxis (or chemorepulsion). OP-positive chemotaxis is prominent in gradients with low maximal concentrations of S1P, whereas such behavior is minimal in fields with high maximal S1P concentrations. This reverse-directional behavior is caused by S1PR2-mediated chemorepulsion acting to override S1PR1 upgradient motion. S1PR2-deficient mice exhibit moderate osteopetrosis as a result of a decrease in osteoclastic bone resorption, suggesting that S1PR2 contributes to OP localization on the bones mediated by chemorepulsion away from the blood where S1P levels are high. Inhibition of S1PR2 function by the antagonist JTE013 changed the migratory behavior of monocytoid cells, including OPs, and relieved osteoporosis in a mouse model by limiting OP localization and reducing the number of mature OCs attached to the bone surface. Thus, reciprocal regulation of S1P-dependent chemotaxis controls bone remodeling by finely regulating OP localization. This regulatory axis may be promising as a therapeutic target in diseases affecting OC-dependent bone remodeling.
Laboratory of Biological Imaging, WPI-Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. mishii@ifrec.osaka-u.ac.jp
Masaru
M
Ishii
Junichi
J
Kikuta
Yutaka
Y
Shimazu
Martin
M
Meier-Schellersheim
Ronald N
RN
Germain
D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects*; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D005434:Flow Cytometry; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000097:blood / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D034622:RNA Interference; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; C471998:JTE 013; D008246:Lysophospholipids; D011720:Pyrazoles; D011725:Pyridines; D053245:RANK Ligand; D019707:Receptors, Chemokine; D049349:Receptors, Lysosphingolipid; D011993:Recombinant Fusion Proteins; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse; D049452:Green Fluorescent Proteins; C060506:sphingosine 1-phosphate; D005982:Glutathione Transferase; D013110:Sphingosine