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Reduced incidence and severity of experimental autoimmune arthritis in mice expressing catalytically inactive A disintegrin and metalloproteinase 8 (ADAM8)
- Publication Year :
- 2009
- Publisher :
- Blackwell Science Inc, 2009.
-
Abstract
- Summary 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 (ADAM8EQ) 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, ADAM8EQ mice demonstrated decreased incidence and severity of clinical arthritis compared to wild-type mice. Histological examination of paw joints from ADAM8EQ 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.
- Subjects :
- Lipopolysaccharides
Male
Chemokine
Inflammatory arthritis
Immunology
Arthritis
Glutamic Acid
Inflammation
Mice, Transgenic
medicine.disease_cause
Severity of Illness Index
Catalysis
Autoimmunity
Arthritis, Rheumatoid
Mice
Antigens, CD
medicine
Immunology and Allergy
Animals
Point Mutation
Collagen Type II
Cells, Cultured
Autoantibodies
Oligonucleotide Array Sequence Analysis
Autoimmune disease
biology
business.industry
Gene Expression Profiling
Membrane Proteins
Organ Size
medicine.disease
Arthritis, Experimental
ADAM Proteins
Mice, Inbred DBA
Rheumatoid arthritis
biology.protein
Animal Studies
Disease Progression
Cytokines
medicine.symptom
business
ADAM8
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....7f3eb5caec83ba3366838c4a79d7f338