Regulation of joint destruction and inflammation by p53 in collagen-induced arthritis.
The role of the tumor suppressor p53 as a key regulator of inflammation was examined in murine collagen-induced arthritis (CIA), a model of rheumatoid arthritis. Wild-type DBA/1 mice develop progressive arthritis in this model, in which p53 expression and apoptosis are evident in the synovial cells. In contrast, the joints of p53(-/-) DBA/1 animals with CIA showed increased severity of arthritis using clinical and histological scoring methods with almost no apoptosis. Consistent with this, collagenase-3 expression and cytokine production (interleukin-1 and interleukin-6) in the joints of p53(-/-) mice with CIA were significantly greater than in wild-type mice. Anti-collagen antibody titers, however, were not different. Therefore, p53 expression occurs during inflammation and acts to suppress local inflammatory responses. Because mutations in p53 have been described in the synovial membrane of rheumatoid arthritis patients, the loss of p53 function in synoviocytes or other cells in the joint because of dominant-negative mutations might contribute to invasion and destruction of the joint in this disease.
Yamanishi
Yuji
Y
University of California at San Diego School of Medicine, La Jolla. La Jolla, California 92093, USA.
Boyle
David L
DL
Pinkoski
Michael J
MJ
Mahboubi
Artin
A
Lin
Tesu
T
Han
Zuoning
Z
Zvaifler
Nathan J
NJ
Green
Douglas R
DR
Firestein
Gary S
GS
D000818:Animals; D000906:Antibodies / Q000032:analysis; D017209:Apoptosis; D001168:Arthritis / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology*; D002455:Cell Division; D003094:Collagen; D024043:Collagen Type II / Q000276:immunology; D017364:Collagenases / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007596:Joints / Q000473:pathology*; D053509:Matrix Metalloproteinase 13; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout / Q000235:genetics; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000473:pathology / Q000503:physiopathology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000906:Antibodies; D024043:Collagen Type II; D007375:Interleukin-1; D015850:Interleukin-6; D016159:Tumor Suppressor Protein p53; D003094:Collagen; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse