High affinity glycosaminoglycan and autoantigen interaction explains joint specificity in a mouse model of rheumatoid arthritis

Daniel R. Studelska, Laura Mandik-Nayak, Xiaodong Zhou, Jing Pan, Peter Weiser, Lynda M. McDowell, Hong Lu, Helen Liapis, Paul M. Allen, Fei F. Shih, Lijuan Zhang

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2354-2362
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number4
DOIs
StatePublished - Jan 23 2009

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