Autoantibody modulation of cartilage turnover in rheumatoid arthritis

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ABSTRACT Rheumatoid arthritis (RA) affects 0.5-1% of the world population. RA is characterized by autoantibody production, synovial inflammation and swelling, and destruction of cartilage and bone resulting in progressive disability. It is not known whether early reactivities, such as anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), are pathogenic, regulatory, or only a secondary phenomenon not related to the pathogenesis. A possible scenario is that RA occurs when the autoimmune response switches to targeting joints, in particular proteins within or adhering to cartilage. Type II collagen the major protein in joint cartilage and is also the target of most known autoantibodies that can induce arthritis. We have obtained evidence that autoimmune reactivities to type II collagen commonly occur in RA patients and may be one of the major mechanisms whereby the disease is initiated. The research plan described herein focuses on antibody modulation of type II collagen processing by matrix metalloproteinase 13 (MMP-13), the main collagenase responsible for degradation of articular cartilage during arthritis. Our hypothesis is as follows. Under normal circumstances, MMP-13 cleaves type II collagen initially at the Gly775-Leu776 bond, followed by further digestion of collagen fragments. In RA, autoantibodies to type II collagen inhibit the action of MMP-13 at different stages, resulting in the stable production of collagen fragments. The collagen fragments could activate the immune system to be more pathogenic or regulatory as well as modify chondrocyte functions, and thereby play a role in the initiation of RA. This represents a novel paradigm for RA onset and progression. To explore this hypothesis, the specific aims are to examine the effects of (1) posttranslational modification of Arg residues to citrulline on MMP-13 processing of type II collagen, (2) RA antibodies on MMP-13 processing of type II collagen and subsequent fragment production, and (3) MMP-13 derived type II collagen fragments on chondrocyte activity and in in vivo mouse models of RA. These aims will incorporate a variety of strategies, including enzyme kinetic analysis of hydrolysis of triple-helical structures, proteomics analysis of type II collagen fragments, and proliferation, qRT-PCR, FACS, and western blot analysis of chondrocytes. The present study will shed new light on the roles of specific anti- collagen antibodies in RA progression.