Combination of Two Monoclonal Anti–Citrullinated Protein Antibodies Induced Tenosynovitis, Pain, and Bone Loss in Mice in a Peptidyl Arginine Deiminase‐4–Dependent Manner

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 75; no. 2; pp. 164 - 170
• Main Authors: Krishnamurthy, Akilan, Circiumaru, Alexandra, Sun, Jitong, Kisten, Yogan, Damberg, Peter, Sakuraba, Koji, Sandor, Katalin, Jarvoll, Patrik, Zhou, Tunhe, Malmström, Vivianne, Svensson, Camilla I., Hensvold, Aase, Catrina, Anca I., Klareskog, Lars, Réthi, Bence
• Format: Journal Article
• Language: English
• Published: Boston, USA Wiley Periodicals, Inc 01.02.2023; Wiley Subscription Services, Inc
• Subjects: Animals; Ankle; Anti-Citrullinated Protein Antibodies; Antibodies; Arginine deiminase; Arthritis; Arthritis, Rheumatoid; Autoantibodies; Bone imaging; Bone loss; Brief Report; Cancellous bone; Citrulline; Computer architecture; Hyperplasia; Joint diseases; Joints (anatomy); Magnetic resonance imaging; Medicin och hälsovetenskap; Mice; Monoclonal antibodies; Pain; Pathogenicity; Pathogens; Plasma cells; Protein-arginine deiminase; Protein-Arginine Deiminase Type 4; Proteins; Rheumatoid Arthritis; Risk analysis; Risk factors; Sheaths; Synovitis; Tendons; Tenosynovitis; Tenosynovitis - diagnostic imaging; Tibia
• ISSN: 2326-5191; 2326-5205; 2326-5205
• DOI: 10.1002/art.42320

Objective 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. We undertook this study to investigate whether 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 4 (PAD4). Methods Monoclonal ACPAs generated from plasma cells of RA patients were transferred to wild‐type and PAD4‐deficient mice. Pain‐like behavior and macroscopic inflammation were monitored for a period of 4 weeks, followed by the analyses of tenosynovitis in the ankle joints using magnetic resonance imaging (MRI) and bone microarchitecture in the tibia using an X‐ray microscope. Microscopic changes in the tendon sheath were analyzed in decalcified ankle joint sections. Results The combination of 2 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−/− mice, the effects of ACPAs on pain‐like behavior, tenosynovitis, and bone loss were significantly reduced. Conclusion Monoclonal ACPAs can induce tenosynovitis in addition to pain and bone loss via mechanisms dependent on PAD4‐mediated citrullination.