title: Regulation of osteoclast homeostasis and inflammatory bone loss by MFG-E8.
abstract: The glycoprotein milk fat globule-epidermal growth factor factor 8 (MFG-E8) is expressed in several tissues and mediates diverse homeostatic functions. However, whether it plays a role in bone homeostasis has not been established. In this study, we show for the first time, to our knowledge, that osteoclasts express and are regulated by MFG-E8. Bone marrow-derived osteoclast precursors from MFG-E8-deficient (Mfge8(-/-)) mice underwent increased receptor activator of NF-κB ligand-induced osteoclastogenesis, leading to enhanced resorption pit formation compared with wild-type controls. Consistently, exogenously added MFG-E8 inhibited receptor activator of NF-κB ligand-induced osteoclastogenesis from mouse or human osteoclast precursors. Upon induction of experimental periodontitis, an oral inflammatory disease characterized by loss of bone support of the dentition, Mfge8(-/-) mice exhibited higher numbers of osteoclasts and more bone loss than did wild-type controls. Accordingly, local microinjection of anti-MFG-E8 mAb exacerbated periodontal bone loss in wild-type mice. Conversely, microinjection of MFG-E8 inhibited bone loss in experimental mouse periodontitis. In comparison with wild-type controls, Mfge8(-/-) mice also experienced >60% more naturally occurring chronic periodontal bone loss. In conclusion, MFG-E8 is a novel homeostatic regulator of osteoclasts that could be exploited therapeutically to treat periodontitis and perhaps other immunological disorders associated with inflammatory bone loss.
authors: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors: Toshiharu
authors: T
authors: Abe
authors: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors: Jieun
authors: J
authors: Shin
authors: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors: Kavita
authors: K
authors: Hosur
authors: Center for Cancer Research, Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Mark C
authors: MC
authors: Udey
authors: Department of Medicine, Institute for Clinical Chemistry and Laboratory Medicine, Dresden University of Technology, 01307 Dresden, Germany; and Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Dresden University of Technology, 01307 Dresden, Germany.
authors: Triantafyllos
authors: T
authors: Chavakis
authors: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; geoh@upenn.edu.
authors: George
authors: G
authors: Hajishengallis
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001862:Bone Resorption / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins / Q000096:biosynthesis / Q000235:genetics; D010010:Osteoclasts / Q000276:immunology* / Q000473:pathology*; D010518:Periodontitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053245:RANK Ligand / Q000008:administration & dosage / Q000009:adverse effects; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000954:Antigens, Surface; D018836:Inflammation Mediators; C098942:MFGE8 protein, human; D008894:Milk Proteins; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse