The Open Arthritis Journal

2009, 2 : 7-13
Published online 2009 February 26. DOI: 10.2174/1876539400902010007
Publisher ID: TOARTHJ-2-7

RESEARCH ARTICLE
 Disruption of Rankl/Rank Signaling Reduces TNF-Induced Joint Inflammation In Vivo

Zhenqiang Yao1 , Ping Li2 , Qian Zhang1 , Ruolin Guo1 , Edward M. Schwarz2 , Brendan F. Boyce1,2 and Lianping Xing, *,1,2
1 Department of Pathology and Laboratory Medicine
2 Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA

* Address correspondence to this author at the Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, New York, 14642, USA; Tel: 585-273-4090; Fax: 585-756-4468; E-mail: lianping_xing@urmc.rochester.edu

ABSTRACT

TNF is a dominant inflammatory cytokine that is over-produced in the joints of patients with rheumatoid arthritis, as well as animal models of this disease. It promotes bone destruction and inflammation through stimulation of osteoclast formation and activation. While it has been established that the RANKL/RANK system is essential for TNF-induced osteoclast formation and bone erosion in vivo, its role in TNF-induced inflammation remains poorly understood and controversial. Here, we report that genetic and biologic disruption of the RANKL/RANK signaling eliminates knee joint inflammation in TNF-Tg/RANKL-/-, TNF-Tg/RANK-/- and RANK:Fc treated-TNF-Tg mice as determined by functional assessments and histomorphometry. Among several potential mechanisms that could be responsible for this decrease in inflammation, we found that RANKL synergizes with TNF to stimulate TNF production by osteoclast precursors. Thus, blockade of RANKL/RANK signaling may be a viable therapeutic strategy to prevent inflammation and bone loss in diseases where elevated TNF is a key pathogenic factor.