Combination of two monoclonal ACPAs induced tenosynovitis, pain and bone loss in mice in a Peptidyl Arginine Deiminase-4 dependent manner.

The appearance of anti-citrullinated protein antibodies (ACPAs) in the circulation represents a major risk factor for developing rheumatoid arthritis (RA). Patient-derived ACPAs have been shown to induce pain and bone erosion in mice suggesting an active role in the pathogenicity of RA. Here we investigated if ACPAs can induce tenosynovitis, an early sign of RA, in addition to pain and bone loss and whether these symptoms are dependent on peptidyl arginine deiminase (PAD4).Monoclonal ACPAs generated from plasma cells of RA patients were transferred to wildtype and PAD4-deficient mice. Pain-like behavior and macroscopic inflammation were monitored for a period of four weeks, followed by the analyses of tenosynovitis in the ankle joints using magnetic resonance imaging (MRI) and bone micro-architecture in the tibia using X-ray microscope. Microscopic changes in the tendon sheath were analyzed in decalcified ankle joint sections.Combination of two monoclonal ACPAs (1325:04C03 and 1325:01B09) induced long-lasting pain-like behavior and trabecular bone loss in mice. Although no synovitis was observed macroscopically, we detected tenosynovitis in the ACPA-injected mice by MRI. Microscopic analyses of the joints revealed a cellular hyperplasia and a consequent enlargement of the tendon sheath in the ACPA-treated group. In PAD4-deficient mice the effects of ACPAs on pain-like behavior, tenosynovitis and bone loss were significantly reduced.Monoclonal ACPAs can induce tenosynovitis in addition to pain and bone loss via mechanisms dependent on PAD4-mediated citrullination. This article is protected by copyright. All rights reserved.