title: Loss of milk fat globule-epidermal growth factor 8 (MFG-E8) in mice leads to low bone mass and accelerates ovariectomy-associated bone loss by increasing osteoclastogenesis.
abstract: Milk fat globule-epidermal growth factor 8 (MFG-E8) is a glycoprotein that controls the engulfment of apoptotic cells and exerts inflammation-modulatory effects. Recently, it has been implicated in osteoclastogenesis and the pathogenesis of inflammatory periodontal bone loss, but its role in physiological bone homeostasis is still not well defined. Here, we evaluated the influence of MFG-E8 on osteoblasts and osteoclasts and its impact on bone remodeling in healthy and ovariectomized mice as a model for post-menopausal osteoporosis. Total and trabecular bone mineral densities at the lumbar spine in 6-week-old MFG-E8 KO mice were reduced by 11% (p < 0.05) and 17% (p < 0.01), respectively, as compared to wild-type (WT) mice. Accordingly, serum levels of the bone formation marker P1NP were decreased by 37% (p < 0.01) in MFG-E8 KO mice as were the ex vivo mineralization capacity and expression of osteoblast genes (Runx2, alkaline phosphatase, osteocalcin) in MFG-E8 KO osteoblasts. In contrast, serum bone resorption markers CTX1 and TRAP5b were increased by 30% and 60% (p < 0.05), respectively, in MFG-E8 KO mice. Furthermore, bone marrow macrophages from MFG-E8-KO mice differentiated more effectively into osteoclasts, as compared to WT cells. MFG-E8-deficient osteoclasts displayed increased bone resorption ex vivo, which could be reversed by the presence of recombinant MFG-E8. To determine the significance of the enhanced osteoclastogenesis in MFG-E8 KO mice, we performed an ovariectomy, which is associated with bone loss due to increased osteoclast activity. Indeed, MFG-E8 KO mice lost 12% more trabecular bone density than WT mice after ovariectomy. Together, these data indicate that MFG-E8 controls steady-state and pathological bone turnover and may therefore represent a new target gene in the treatment of bone diseases.
authors: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Germany.
authors: Kathrin
authors: K
authors: Sinningen
authors: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Germany.
authors: Elise
authors: E
authors: Albus
authors: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Germany.
authors: Sylvia
authors: S
authors: Thiele
authors: Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Germany.
authors: Sylvia
authors: S
authors: Grossklaus
authors: Electron Microscopy Facility, Center for Regenerative Therapies Dresden, Germany.
authors: Thomas
authors: T
authors: Kurth
authors: Dermatology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors: Mark C
authors: MC
authors: Udey
authors: Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Germany; DFG Research Center for Regenerative Therapies Dresden, Germany.
authors: Triantafyllos
authors: T
authors: Chavakis
authors: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Germany; DFG Research Center for Regenerative Therapies Dresden, Germany.
authors: Lorenz C
authors: LC
authors: Hofbauer
authors: Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Germany. Electronic address: martina.rauner@uniklinikum-dresden.de.
authors: Martina
authors: M
authors: Rauner
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000502:physiology*; D015519:Bone Density; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D008894:Milk Proteins / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology*; D010024:Osteoporosis / Q000209:etiology / Q000503:physiopathology*; D010052:Ovariectomy
chemical_list: D000954:Antigens, Surface; C490919:Mfge8 protein, mouse; D008894:Milk Proteins
keywords: Bone homeostasis; MFG-E8; Osteoblast; Osteoclast