TY - JOUR
T1 - Bim deficiency leads to exacerbation and prolongation of joint inflammation in experimental arthritis
AU - Scatizzi, John C.
AU - Bickel, Emily
AU - Hutcheson, Jack
AU - Haines, G. Kenneth
AU - Perlman, Harris
PY - 2006/10
Y1 - 2006/10
N2 - Objective: Rheumatoid arthritis (RA) is characterized by hyperplasia of the synovial lining, inflammation, 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, experimental 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 sections were used to determine the severity of arthritis. The serum and ankles were examined for production of chemokines and cytokines using enzyme-linked immunosorbent 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 demonstrate 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.
AB - Objective: Rheumatoid arthritis (RA) is characterized by hyperplasia of the synovial lining, inflammation, 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, experimental 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 sections were used to determine the severity of arthritis. The serum and ankles were examined for production of chemokines and cytokines using enzyme-linked immunosorbent 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 demonstrate 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.
UR - http://www.scopus.com/inward/record.url?scp=33750302629&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33750302629&partnerID=8YFLogxK
U2 - 10.1002/art.22133
DO - 10.1002/art.22133
M3 - Article
C2 - 17009248
AN - SCOPUS:33750302629
SN - 0004-3591
VL - 54
SP - 3182
EP - 3193
JO - Arthritis and rheumatism
JF - Arthritis and rheumatism
IS - 10
ER -