title: Reduced incidence and severity of experimental autoimmune arthritis in mice expressing catalytically inactive A disintegrin and metalloproteinase 8 (ADAM8).
abstract: A disintegrin and metalloproteinase 8 (ADAM8), a catalytically active member of the ADAMs family of enzymes, is expressed primarily on immune cells and thus probably involved in inflammatory responses. ADAM8 is also produced by chondrocytes, and recombinant ADAM8 can induce cartilage catabolism. We therefore decided to test the role of ADAM8 in autoimmune inflammatory arthritis using transgenic mice expressing catalytically inactive ADAM8. Transgenic DBA/1J mice expressing an inactivating point mutation in the ADAM8 gene to change Glu330 to Gln330 (ADAM8(EQ)) were generated to evaluate the proteolytic function of ADAM8 in an lipopolysaccharide-synchronized collagen-induced arthritis (LPS-CIA) model of autoimmune arthritis. The systemic inflammatory reaction to LPS was also evaluated in these mice. Expression profiling of paw joints from wild-type mice revealed that ADAM8 mRNA levels increased at the onset of clinical arthritis and correlated well with cellular macrophage markers. When subjected to LPS-CIA, ADAM8(EQ) mice demonstrated decreased incidence and severity of clinical arthritis compared to wild-type mice. Histological examination of paw joints from ADAM8(EQ) mice confirmed marked attenuation of synovial inflammation, cartilage degradation and bone resorption when compared to wild-type mice. However, transgenic mice and wild-type mice responded similarly to LPS-induced systemic inflammation with regard to mortality, organ weights, neutrophil sequestration and serum cytokine/chemokine production. We conclude that ADAM8 proteolytic activity plays a key role in the development of experimental arthritis and may thus be an attractive target for the treatment of arthritic disorders while minimizing risk of immunocompromise.
authors.affiliation: Pfizer Global Research and Development, Chesterfield, MO 63017, USA. marc.d.zack@pfizer.com
authors.forename: M D
authors.initials: MD
authors.lastname: Zack
authors.forename: M A
authors.initials: MA
authors.lastname: Melton
authors.forename: J L
authors.initials: JL
authors.lastname: Stock
authors.forename: C E
authors.initials: CE
authors.lastname: Storer
authors.forename: R A
authors.initials: RA
authors.lastname: Barve
authors.forename: J C
authors.initials: JC
authors.lastname: Minnerly
authors.forename: D J
authors.initials: DJ
authors.lastname: Weiss
authors.forename: J A
authors.initials: JA
authors.lastname: Stejskal
authors.forename: M D
authors.initials: MD
authors.lastname: Tortorella
authors.forename: J R
authors.initials: JR
authors.lastname: Turk
authors.forename: K M
authors.initials: KM
authors.lastname: Shevlin
authors.forename: A-M
authors.initials: AM
authors.lastname: Malfait
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis; D002384:Catalysis; D002478:Cells, Cultured; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D020869:Gene Expression Profiling / Q000379:methods; D018698:Glutamic Acid / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D009929:Organ Size; D017354:Point Mutation; D012720:Severity of Illness Index
chemical_list: D015703:Antigens, CD; D001323:Autoantibodies; D024043:Collagen Type II; D016207:Cytokines; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D018698:Glutamic Acid; D051722:ADAM Proteins; C489402:Adam8 protein, mouse