title: Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis.
abstract: Bone surfaces attract hematopoietic and nonhematopoietic cells, such as osteoclasts (OCs) and osteoblasts (OBs), and are targeted by bone metastatic cancers. However, the mechanisms guiding cells toward bone surfaces are essentially unknown. Here, we show that the Gαi protein-coupled receptor (GPCR) EBI2 is expressed in mouse monocyte/OC precursors (OCPs) and its oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-OHC) is secreted abundantly by OBs. Using in vitro time-lapse microscopy and intravital two-photon microscopy, we show that EBI2 enhances the development of large OCs by promoting OCP motility, thus facilitating cell-cell interactions and fusion in vitro and in vivo. EBI2 is also necessary and sufficient for guiding OCPs toward bone surfaces. Interestingly, OCPs also secrete 7α,25-OHC, which promotes autocrine EBI2 signaling and reduces OCP migration toward bone surfaces in vivo. Defective EBI2 signaling led to increased bone mass in male mice and protected female mice from age- and estrogen deficiency-induced osteoporosis. This study identifies a novel pathway involved in OCP homing to the bone surface that may have significant therapeutic potential.
authors.affiliation: Department of Immunobiology and Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Erin
authors.initials: E
authors.lastname: Nevius
authors.affiliation: Department of Immunobiology and Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Flavia
authors.initials: F
authors.lastname: Pinho
authors.affiliation: Department of Immunobiology and Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Meera
authors.initials: M
authors.lastname: Dhodapkar
authors.affiliation: Department of Immunobiology and Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Huiyan
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Immunobiology and Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Kristina
authors.initials: K
authors.lastname: Nadrah
authors.affiliation: Department of Immunobiology and Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Horowitz
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences and WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kikuta
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences and WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Department of Immunobiology and Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06510 joao.pereira@yale.edu.
authors.forename: João P
authors.initials: JP
authors.lastname: Pereira
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D005260:Female; D006706:Homeostasis; D006888:Hydroxycholesterols / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology
chemical_list: C543809:Gpr183 protein, mouse; D006888:Hydroxycholesterols; D043562:Receptors, G-Protein-Coupled