title: Oral administration of bovine milk derived extracellular vesicles attenuates arthritis in two mouse models.
abstract: METHODS
  This study shows the effect of bovine milk derived extracellular vesicles (BMEVs) on spontaneous polyarthritis in IL-1Ra-deficient mice and collagen-induced arthritis.
  
  
  RESULTS
  BMEVs were isolated from semi-skimmed milk by ultracentrifugation and the particle size was around 100 nm by dynamic light scattering and electron microscopy. BMEVs expressed exosome marker CD63, immunoregulatory microRNA's (miR-30a, -223, -92a), and milk-specific beta-casein and beta-lactoglobulin mRNA. In vitro, PKH-67-labeled BMEVs were taken up by RAW264.7, splenocytes, and intestinal cells as determined by flow cytometry and confocal microscopy. IL-1Ra(-/-) mice received BMEVs by daily oral gavage starting at wk 5 till 15 after birth and collagen-induced arthritis mice via their drinking water starting 1 wk before immunization till day 40. Macroscopically, BMEV treatment delayed the onset of arthritis and histology showed diminished cartilage pathology and bone marrow inflammation in both models. BMEV treatment also reduced the serum levels of MCP-1 and IL-6 and their production by splenic cells. BMEV treatment diminished the anticollagen IgG2a levels, which was accompanied by reduced splenic Th1 (Tbet) and Th17 (RORγT) mRNA.
  
  
  CONCLUSIONS
  This is the first report that oral delivery of BMEVs ameliorates experimental arthritis and this warrants further research to determine whether this beneficial effect can be seen in rheumatoid arthritis patients.
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Onno J
authors.initials: OJ
authors.lastname: Arntz
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Bartijn C H
authors.initials: BC
authors.lastname: Pieters
authors.affiliation: Department of Nutrition, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Marina C
authors.initials: MC
authors.lastname: Oliveira
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mathijs G A
authors.initials: MG
authors.lastname: Broeren
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Miranda B
authors.initials: MB
authors.lastname: Bennink
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: de Vries
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Peter L E M
authors.initials: PL
authors.lastname: van Lent
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: van der Kraan
authors.affiliation: Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Fons A J
authors.initials: FA
authors.lastname: van de Loo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000628:therapy*; D002364:Caseins / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000097:blood; D003094:Collagen / Q000633:toxicity; D055354:Exosomes / Q000235:genetics / Q000378:metabolism; D000067128:Extracellular Vesicles / Q000378:metabolism*; D005819:Genetic Markers; D007074:Immunoglobulin G / Q000097:blood; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D007782:Lactoglobulins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008892:Milk / Q000737:chemistry*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D010316:Particle Size; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D060149:Tetraspanin 30 / Q000235:genetics / Q000378:metabolism
chemical_list: D002364:Caseins; C491768:Ccl2 protein, mouse; C554587:Cd63 protein, mouse; D018932:Chemokine CCL2; D005819:Genetic Markers; C507764:Il1rn protein, mouse; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D007782:Lactoglobulins; C544877:MIRN223 microRNA, mouse; D035683:MicroRNAs; C534715:Mirn30d microRNA, mouse; C541873:Mirn92 microRNA, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger; D060149:Tetraspanin 30; D003094:Collagen
keywords: Exosomes; Immunity; MicroRNA; Milk; Rheumatoid arthritis