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a The Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA b Department of Radiology, University of Rochester, Rochester, New York, USA c Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA d Centocor R&D Inc., Radnor, Pennsylvania, USA
Key Words: inflammatory arthritis • animal model • in vivo imaging • MRI • lymph node • lymphangiogenesis
Address for correspondence: Dr. Edward M. Schwarz, The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, NY 14642. Voice: 585-275-3063; fax: 585-275-1121. Edward_Schwarz{at}URMC.Rochester.edu
While erosion and tissue necrosis are the end-stage result of inflammatory arthritis, factors that can predict their initiation and severity are unknown. In an effort to identify these prognostic factors we developed contrast-enhanced (CE)-magnetic resonance imaging (MRI) for the mouse knee to assess the pathogenesis of inflammatory arthritis. Using this approach to study synovitis and draining lymph node (LN) function we first demonstrated that the LNs of TNF-Tg mice at 5 months are significantly larger and have greater enhancement in comparison to wild-type (WT) mice. This difference correlated with the abundance of dilated LYVE-1+ sinuses in the draining LNs. Dynamic CE-MRI further demonstrated differences between TNF-Tg and WT mice in the kinetics of LN enhancement. We established an LN capacity (LNcap) measurement that is a function of both volume and CE. We demonstrated that TNF-Tg mice have a 15-fold increase over WT levels at 5 months age (P < 0.001). Amelioration of arthritis with anti-TNF therapy resulted in a significant decrease in LNcap (P < 0.0001) that approached WT levels within 4 weeks. Interestingly, this functional decrease was not associated with a reduction of lymphatic vessels, which persist after therapy in both LNs and synovium. To assess the relationship between draining LN function and synovitis, a regression analysis was performed that demonstrated a significant negative correlation (R2 = 0.63, P = 0.01) between LNcap and synovial volume. TNF-Tg mice with a lower LNcap display an accelerated progression of arthritis. These results indicate a protective function of enhanced lymphatic drainage in inflammatory arthritis.
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