ARTHRITIS & RHEUMATISM Vol. 54, No. 10, October 2006, pp 3182–3193 DOI 10.1002/art.22133 © 2006, American College of Rheumatology Bim Deficiency Leads to Exacerbation and Prolongation of Joint Inflammation in Experimental Arthritis John C. Scatizzi, 1 Emily Bickel, 1 Jack Hutcheson, 1 G. Kenneth Haines, III, 2 and Harris Perlman 1 Objective: Rheumatoid arthritis (RA) is charac- terized by hyperplasia of the synovial lining, inflamma- tion, and destruction of cartilage and bone. Since there are only a few detectable cells undergoing apoptosis in the joint, it is possible that a defect in apoptosis may contribute to synovial hyperplasia. This study sought to identify and characterize the direct role of apoptotic regulators in a mouse model of inflammatory arthritis. Methods. Using a serum transfer model, experi- mental arthritis was induced in mice lacking the proapoptotic Bcl-2 family genes Bak (Bak / ), Bax (Bax / ), or Bim (Bim / ), as compared with wild-type (WT) control mice. Physical examination for edema of the ankles and histopathologic analysis of ankle sec- tions were used to determine the severity of arthritis. The serum and ankles were examined for production of chemokines and cytokines using enzyme-linked immu- nosorbent or Luminex-based assays. Results. Bim / mice displayed increased severity and prolongation of arthritis. In contrast, Bak / and Bax / mice showed no difference in the severity of arthritis as compared with WT mice. In addition, Bim / mice had elevated levels of proinflammatory chemokines and cytokines, decreased joint and serum production of antiinflammatory cytokines, fewer TUNEL-positive cells, and reduced levels of active caspase 3 as compared with WT mice. Conclusion. These studies are the first to demon- strate a role for the proapoptotic Bcl-2 protein Bim in the effector phase of RA. The findings indicate that Bim potentially functions to repress the effector phase of arthritis by regulating the milieu of the joint and serum, and by inducing apoptosis. Rheumatoid arthritis (RA) is a chronic inflam- matory and destructive arthropathy of unknown etiology (1). The disease is characterized by infiltration of lym- phocytes and macrophages, hyperplasia of the synovial lining, and destruction of cartilage and bone. The nor- mal synovial lining consists of 1–2 cell layers, whereas this increases in RA to at least 10 cell layers. Synovio- cytes are one of the central contributors to the develop- ment of pannus and to the destruction of cartilage and bone. Although multiple factors lead to hyperplasia of the synovial lining, one potential mechanism may be a resistance of synoviocytes to apoptosis (2). Although the RA joint is replete with noxious molecules, including reactive oxygen species and Fas ligand–expressing cells, histologic evidence of apoptosis is rarely observed by electron microscopy analysis of RA synovial tissue (3,4). We have prevously shown a low level of apoptosis that peaks with the severity of disease in a rat adjuvant- induced arthritis (AIA) model (5). Induction of apopto- sis in the joints of rodents (6–8) results in the ameliora- tion of inflammatory arthritis. In addition, patients with pauciarticular, compared with polyarticular, juvenile chronic arthritis display enhanced mononuclear cell apoptosis in the synovial tissue (9). These findings indicate that increased apoptosis may be associated with an improved clinical outcome. However, although the majority of studies have examined the applicability of inducing apoptosis in rodents, few studies have directly Mr. Scatizzi’s work was supported by an American Heart Association grant (AHA-0515499Z). Mr. Hutcheson’s work was sup- ported by an American College of Rheumatology research grant. Dr. Perlman’s work was supported by grants from the NIH (AR-02147 and AR-050250). 1 John C. Scatizzi, BS, Emily Bickel, BS, Jack Hutcheson, BS, Harris Perlman, PhD: Saint Louis University, St. Louis, Missouri; 2 G. Kenneth Haines, III, MD: Northwestern University, Chicago, Illinois. Address correspondence and reprint requests to Harris Perl- man, PhD, Saint Louis University, School of Medicine, Department of Molecular Microbiology & Immunology, 1402 South Grand Boule- vard, St. Louis, MO 63104. E-mail: perlmanh@slu.edu. Submitted for publication September 13, 2005; accepted in revised form June 26, 2006. 3182