title: Mannan-Binding Lectin-Associated Serine Protease 1/3 Cleavage of Pro-Factor D into Factor D In Vivo and Attenuation of Collagen Antibody-Induced Arthritis through Their Targeted Inhibition by RNA Interference-Mediated Gene Silencing.
abstract: The complement system is proposed to play an important role in the pathogenesis of rheumatoid arthritis (RA). The complement system mannan-binding lectin-associated serine proteases (MASP)-1/3 cleave pro-factor D (proDf; inactive) into Df (active), but it is unknown where this cleavage occurs and whether inhibition of MASP-1/3 is a relevant therapeutic strategy for RA. In the present study, we show that the cleavage of proDf into Df by MASP-1/3 can occur in the circulation and that inhibition of MASP-1/3 by gene silencing is sufficient to ameliorate collagen Ab-induced arthritis in mice. Specifically, to examine the cleavage of proDf into Df, MASP-1/3-producing Df-/-liver tissue (donor) was transplanted under the kidney capsule of MASP-1/3-/-(recipient) mice. Five weeks after the liver transplantation, cleaved Df was present in the circulation of MASP-1/3-/-mice. To determine the individual effects of MASP-1/3 and Df gene silencing on collagen Ab-induced arthritis, mice were injected with scrambled, MASP-1/3-targeted, or Df-targeted small interfering RNAs (siRNAs). The mRNA levels for MASP-1 and -3 decreased in the liver to 62 and 58%, respectively, in mice injected with MASP-1/3 siRNAs, and Df mRNA decreased to 53% in the adipose tissue of mice injected with Df siRNAs; additionally, circulating MASP-1/3 and Df protein levels were decreased. In mice injected with both siRNAs the clinical disease activity, histopathologic injury scores, C3 deposition, and synovial macrophage/neutrophil infiltration were significantly decreased. Thus, MASP-1/3 represent a new therapeutic target for the treatment of RA, likely through both direct effects on the lectin pathway and indirectly through the alternative pathway.
authors.affiliation: Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; Nirmal.Banda@ucdenver.edu.
authors.forename: Nirmal K
authors.identifier: 0000-0002-5291-5136
authors.initials: NK
authors.lastname: Banda
authors.affiliation: Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Sumitra
authors.identifier: 0000-0001-6935-7962
authors.initials: S
authors.lastname: Acharya
authors.affiliation: School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Robert I
authors.identifier: 0000-0001-8485-6620
authors.initials: RI
authors.lastname: Scheinman
authors.affiliation: Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Mehta
authors.affiliation: Colorado Center for Transplantation Care, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Marilyne
authors.identifier: 0000-0002-3508-0368
authors.initials: M
authors.lastname: Coulombe
authors.affiliation: Department of Immunology, Fukushima Medical University, Fukushima 960-1295, Japan; and.
authors.forename: Minoru
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Immunology, Fukushima Medical University, Fukushima 960-1295, Japan; and.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Sekine
authors.affiliation: Department of Biomedicine, University of Aarhus, 8000 Aarhus, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
authors.affiliation: Department of Immunology, Fukushima Medical University, Fukushima 960-1295, Japan; and.
authors.forename: Teizo
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000628:therapy*; D011416:Complement Factor D / Q000235:genetics / Q000378:metabolism*; D037582:Complement Pathway, Mannose-Binding Lectin; D006801:Humans; D008297:Male; D037601:Mannose-Binding Lectin / Q000378:metabolism; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059748:Proteolysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D037601:Mannose-Binding Lectin; D034741:RNA, Small Interfering; C577328:MASP-1 protein, mouse; D050606:Mannose-Binding Protein-Associated Serine Proteases; D011416:Complement Factor D