title: Milk Fat Globule-Epidermal Growth Factor 8 (MFG-E8) Is a Novel Anti-inflammatory Factor in Rheumatoid Arthritis in Mice and Humans.
abstract: Milk fat globule-epidermal growth factor 8 (MFG-E8) is an anti-inflammatory glycoprotein that mediates the clearance of apoptotic cells and is implicated in the pathogenesis of autoimmune and inflammatory diseases. Because MFG-E8 also controls bone metabolism, we investigated its role in rheumatoid arthritis (RA), focusing on inflammation and joint destruction. The regulation of MFG-E8 by inflammation was assessed in vitro using osteoblasts, in arthritic mice and in patients with RA. K/BxN serum transfer arthritis (STA) was applied to MFG-E8 knock-out mice to assess its role in the pathogenesis of arthritis. Stimulation of osteoblasts with lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α downregulated the expression of MFG-E8 by 30% to 35%. MFG-E8-deficient osteoblasts responded to LPS with a stronger production of pro-inflammatory cytokines. In vivo, MFG-E8 mRNA levels were 52% lower in the paws of collagen-induced arthritic (CIA) mice and 24% to 42% lower in the serum of arthritic mice using two different arthritis models (CIA and STA). Similarly, patients with RA (n = 93) had lower serum concentrations of MFG-E8 (-17%) compared with healthy controls (n = 140). In a subgroup of patients who had a moderate to high disease activity (n = 21), serum concentrations of MFG-E8 rose after complete or partial remission had been achieved (+67%). Finally, MFG-E8-deficient mice subjected to STA exhibited a stronger disease burden, an increased number of neutrophils in the joints, and a more extensive local and systemic bone loss. This was accompanied by an increased activation of osteoclasts and a suppression of osteoblast function in MFG-E8-deficient mice. Thus, MFG-E8 is a protective factor in the pathogenesis of RA and subsequent bone loss. Whether MFG-E8 qualifies as a novel biomarker or therapeutic target for the treatment of RA is worth addressing in further studies.
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Elise
authors.initials: E
authors.lastname: Albus
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Dresden, Germany.|Department of Obstetrics and Gynecology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Sinningen
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Winzer
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Thiele
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Baschant
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Hannemann
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Fantana
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Tausche
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Henri
authors.initials: H
authors.lastname: Wallaschofski
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Grossklaus
authors.affiliation: Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.|DFG Research Center for Regenerative Therapies Dresden, Dresden, Germany.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Udey
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Dresden, Germany.|DFG Research Center for Regenerative Therapies Dresden, Dresden, Germany.
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
mesh_terms: D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D000954:Antigens, Surface / Q000097:blood / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D001862:Bone Resorption / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007596:Joints / Q000473:pathology; D008070:Lipopolysaccharides; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008894:Milk Proteins / Q000097:blood / Q000378:metabolism*; D020556:Neutrophil Infiltration; D014409:Tumor Necrosis Factor-alpha
chemical_list: D000893:Anti-Inflammatory Agents; D000954:Antigens, Surface; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C098942:MFGE8 protein, human; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D014409:Tumor Necrosis Factor-alpha
keywords: INFLAMMATION; MFG-E8; NEUTROPHILS; BONE LOSS; RHEUMATOID ARTHRITIS