Rheumatoid arthritis (RA) is a chronic inflammatory and destructive arthropathy that results in increased morbidity and mortality. The fibroblasts that comprise the synovial lining (synovial fibroblasts), a thin membrane in direct contact with cartilage and bone, are one of the principal cells responsible for the pathogenesis of RA. In RA, the synovial fibroblasts increase in number and produce pro-inflammatory cytokines and matrix-metalloproteinases (MMPs) that promote inflammation and joint destruction. We recently discovered a novel role for the cell cycle inhibitor p21 in RA, namely that p21 not only blocks cell cycle progression, it also reduces the synthesis of IL-6 and MMP-1. p21 expression is reduced in RA compared to osteoarthritis synovial fibroblasts. Restoration of p21 blocks cell cycle progression and suppresses IL-6 and MMP-1 synthesis in RA but not in non-RA synovial fibroblasts. Additionally, restored p21 attenuates the DNA binding activity of AP-1, a transcription factor that is increased during RA and is a known inducer of IL-6 and MMP-1. p21-deficient synovial flbroblasts exhibit a 100-fold increase in IL-6 secretion, a marked increase in IL-6 and MMP-3 mRNA accumulation, and enhanced AP-1 DNA binding activity compared to wild-type cells. In contrast to Rb overexpression, which also induces cell cycle arrest, restoration of p21 in p21-deficient synovial fibroblasts returned IL-6 and MMP-3 to wild-type levels. Based on our data, we hypothesize that p21 suppresses IL-6 and MMP-1 transcription in the normal joint through the inhibition of the AP-1 pathway. In the RA joint, the p21 pathway is defective, resulting in proliferation of synovial fibroblasts and increased synthesis of IL-6 and MMP-1. Accordingly, RA may be treatable by restoring the p21 pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050250-02
Application #
6782749
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Gretz, Elizabeth
Project Start
2003-07-07
Project End
2008-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$285,180
Indirect Cost
Name
Saint Louis University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Tsai, FuNien; Homan, Philip J; Agrawal, Hemant et al. (2017) Bim suppresses the development of SLE by limiting myeloid inflammatory responses. J Exp Med 214:3753-3773
Makinde, Hadijat M; Just, Talia B; Cuda, Carla M et al. (2017) The Role of Microglia in the Etiology and Evolution of Chronic Traumatic Encephalopathy. Shock 48:276-283
Brazee, Patricia L; Soni, Pritin N; Tokhtaeva, Elmira et al. (2017) FXYD5 Is an Essential Mediator of the Inflammatory Response during Lung Injury. Front Immunol 8:623
Tsai, FuNien; Perlman, Harris; Cuda, Carla M (2017) The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis. Clin Immunol 185:74-85
MacLauchlan, Susan; Zuriaga, Maria A; Fuster, José J et al. (2017) Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis. Arthritis Res Ther 19:166
Cuda, Carla M; Pope, Richard M; Perlman, Harris (2016) The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases. Nat Rev Rheumatol 12:543-58
Bharat, Ankit; Bhorade, Sangeeta M; Morales-Nebreda, Luisa et al. (2016) Flow Cytometry Reveals Similarities Between Lung Macrophages in Humans and Mice. Am J Respir Cell Mol Biol 54:147-9
Archer, Amy M; Saber, Rana; Rose, Shawn et al. (2016) ApoE deficiency exacerbates the development and sustainment of a semi-chronic K/BxN serum transfer-induced arthritis model. J Transl Med 14:170
Cuda, Carla M; Misharin, Alexander V; Khare, Sonal et al. (2015) Conditional deletion of caspase-8 in macrophages alters macrophage activation in a RIPK-dependent manner. Arthritis Res Ther 17:291
Huang, Qi-Quan; Perlman, Harris; Birkett, Robert et al. (2015) CD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis. Nat Commun 6:7086

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