High Affinity Glycosaminoglycan and Autoantigen Interaction Explains Joint Specificity in a Mouse Model of Rheumatoid Arthritis

In the K/BxN mouse model of rheumatoid arthritis, autoantibodies specific for glucose-6-phosphate isomerase (GPI) can transfer joint-specific inflammation to most strains of normal mice. Binding of GPI and autoantibody to the joint surface is a prerequisite for joint-specific inflammation. However,...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-01, Vol.284 (4), p.2354-2362
Main Authors: Studelska, Daniel R., Mandik-Nayak, Laura, Zhou, Xiaodong, Pan, Jing, Weiser, Peter, McDowell, Lynda M., Lu, Hong, Liapis, Helen, Allen, Paul M., Shih, Fei F., Zhang, Lijuan
Format: Article
Language:English
Subjects:
Animals
Arthritis, Rheumatoid - immunology
Arthritis, Rheumatoid - metabolism
Arthritis, Rheumatoid - pathology
Autoantigens - immunology
Biocatalysis
Cartilage - metabolism
Disaccharides - metabolism
Disease Models, Animal
Glucose-6-Phosphate Isomerase - metabolism
Glycobiology and Extracellular Matrices
Glycosaminoglycans - chemistry
Glycosaminoglycans - metabolism
Mice
Mice, Inbred BALB C
Molecular Structure
Protein Binding
Substrate Specificity
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Summary:In the K/BxN mouse model of rheumatoid arthritis, autoantibodies specific for glucose-6-phosphate isomerase (GPI) can transfer joint-specific inflammation to most strains of normal mice. Binding of GPI and autoantibody to the joint surface is a prerequisite for joint-specific inflammation. However, how GPI localizes to the joint remains unclear. We show that glycosaminoglycans (GAGs) are the high affinity (83 nm) joint receptors for GPI. The binding affinity and structural differences between mouse paw/ankle GAGs and elbows/knee GAGs correlated with the distal to proximal disease severity in these joints. We found that cartilage surface GPI binding was greatly reduced by either chondroitinase ABC or β-glucuronidase treatment. We also identified several inhibitors that inhibit both GPI/GAG interaction and GPI enzymatic activities, which suggests that the GPI GAG-binding domain overlaps with the active site of GPI enzyme. Our studies raise the possibility that GAGs are the receptors for other autoantigens involved in joint-specific inflammatory responses.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M806458200