title: Macrophage Migration Inhibitory Factor (MIF) Supports Homing of Osteoclast Precursors to Peripheral Osteolytic Lesions.
abstract: By binding to its chemokine receptor CXCR4 on osteoclast precursor cells (OCPs), it is well known that stromal cell-derived factor-1 (SDF-1) promotes the chemotactic recruitment of circulating OCPs to the homeostatic bone remodeling site. However, the engagement of circulating OCPs in pathogenic bone resorption remains to be elucidated. The present study investigated a possible chemoattractant role of macrophage migration inhibitory factor (MIF), another ligand for C-X-C chemokine receptor type 4 (CXCR4), in the recruitment of circulating OCPs to the bone lytic lesion. To accomplish this, we used Csf1r-eGFP-knock-in (KI) mice to establish an animal model of polymethylmethacrylate (PMMA) particle-induced calvarial osteolysis. In the circulating Csf1r-eGFP+ cells of healthy Csf1r-eGFP-KI mice, Csf1r+/CD11b+ cells showed a greater degree of RANKL-induced osteoclastogenesis compared to a subset of Csf1r+/RANK+ cells in vitro. Therefore, Csf1r-eGFP+/CD11b+ cells were targeted as functionally relevant OCPs in the present study. Although expression of the two cognate receptors for MIF, CXCR2 and CXCR4, was elevated on Csf1r+/CD11b+ cells, transmigration of OCPs toward recombinant MIF in vitro was facilitated by ligation with CXCR4, but not CXCR2. Meanwhile, the level of PMMA-induced bone resorption in calvaria was markedly greater in wild-type (WT) mice compared to that detected in MIF-knockout (KO) mice. Interestingly, in contrast to the elevated MIF, diminished SDF-1 was detected in a particle-induced bone lytic lesion of WT mice in conjunction with an increased number of infiltrating CXCR4+ OCPs. However, such diminished SDF-1 was not found in the PMMA-injected calvaria of MIF-KO mice. Furthermore, stimulation of osteoblasts with MIF in vitro suppressed their production of SDF-1, suggesting that MIF can downmodulate SDF-1 production in bone tissue. Systemically administered anti-MIF neutralizing monoclonal antibody (mAb) inhibited the homing of CXCR4+ OCPs, as well as bone resorption, in the PMMA-injected calvaria, while increasing locally produced SDF-1. Collectively, these data suggest that locally produced MIF in the inflammatory bone lytic site is engaged in the chemoattraction of circulating CXCR4+ OCPs. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Movila
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|Department of Orthodontics, Tokyo Dental College, Tokyo, Japan.
authors.forename: Takenobu
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|School of Dental Medicine, Harvard University, Boston, MA, USA.|Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Albassam
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|School of Dental Medicine, Harvard University, Boston, MA, USA.|Department of Periodontology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Wichaya
authors.initials: W
authors.lastname: Wisitrasameewong
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Howait
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|Research and Development Headquarters, LION Corporation, Kanagawa, Japan.
authors.forename: Tsuguno
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Ruiz-Torruella
authors.affiliation: Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Laila
authors.initials: L
authors.lastname: Bahammam
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|Graduate School of Dentistry, Tohoku University, Sendai, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Van Dyke
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|School of Dental Medicine, Harvard University, Boston, MA, USA.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kawai
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001842:Bone and Bones / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D002460:Cell Line; D002469:Cell Separation; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D055879:Gene Knock-In Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D016130:Immunophenotyping; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D019904:Polymethyl Methacrylate; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D039481:CD11b Antigen; D054377:Chemokine CXCL12; D008263:Macrophage Migration-Inhibitory Factors; D019718:Receptors, CXCR4; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D019904:Polymethyl Methacrylate; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: CXCR4; MIF; OSTEOCLAST PRECURSORS; PARTICLE-INDUCED OSTEOLYTIC LESIONS; SDF-1