Gary Firestein

Director, Clinical and Translational Research Insitute, UC San Diego

Dr. Firestein’s research efforts have focused on the pathogenesis of rheumatoid arthritis (RA). His laboratory helped define the synovial cytokine profile of RA and demonstrated the dominance of macrophage and fibroblast products as opposed to the expected T cell cytokines. These studies contributed to the development of the highly effective anti-TNF approaches in RA. Recently, Dr. Firestein has focused his attention on synoviocyte transformation in RA as a mechanism of joint destruction. His group was the first to describe somatic mutations in the p53 tumor suppressor genes in the RA synovium. The mutations were subsequently demonstrated to be dominant negative and increased the cartilage invasiveness of these cells. Dr. Firestein’s laboratory has also worked extensively on metalloproteinase and cytokine gene regulation in synoviocytes by MAP kinases and NF-kB as well as on novel gene therapy approaches to RA.Dr. Firestein's research efforts have focused on the pathogenesis of rheumatoid arthritis (RA). His laboratory helped define the synovial cytokine profile of RA and demonstrated the dominance of macrophage and fibroblast products as opposed to the expected T cell cytokines. These studies contributed to the development of the highly effective anti-TNF approaches in RA. Recently, Dr. Firestein has focused his attention on synoviocyte transformation in RA as a mechanism of joint destruction. His group was the first to describe somatic mutations in the p53 tumor suppressor genes in the RA synovium. The mutations were subsequently demonstrated to be dominant negative and increased the cartilage invasiveness of these cells. Dr. Firestein's laboratory has also worked extensively on metalloproteinase and cytokine gene regulation in synoviocytes by MAP kinases and NF-kB as well as on novel gene therapy approaches to RA. More recently, his laboratory has defined a novel epigenetic signature in rheumatoid arthritis that could contribute to joint destruction.

  1. Inoue, T, Boyle DL, Corr M, Hammaker D, Davis RJ, Flavell RA, and Firestein GS. MKK3 is a pivotal pathway regulating p38 activation in inflammatory arthritis. Proc. Natl Acad Sci USA, 103:5484-9, 2006. PMCID: 1459381
  2. Boyle DL, Jones TJ, Hammaker D, Svensson CI, Rosengren S, Mauyama K, Sorkin LS, and Firestein GS. Regulation of peripheral inflammation by spinal p38 MAP kinase in rats. PLoS Medicine, 3:1617-24, 2006. PMCID: 1175047
  3. Hammaker DR, Boyle DL, Inoue T, and Firestein GS. Regulation of the JNK pathway by TGF-beta activated kinase 1 in rheumatoid arthritis synoviocytes. Arthritis Res Ther, 9:R57, 2007. PMCID: 2206340
  4. Waldburger JM, Boyle DL, Pavlov VA, Tracey KJ, and Firestein GS. Acetylcholine regulates synoviocyte cytokine expression via the alpha7 nicotinic receptor, Arthritis Rheum, 58:3439-49, 2008. PMID: 18975306
  5. Yoshizawa T, Hammaker D, Sweeney SE, Boyle DL, and Firestein GS. Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAP kinase kinases. J Immunol, 181:3252-8, 2008. PMCID: 2725405
  6. Corr MP, Boyle DL, Ronacher L, Flores N, and Firestein GS. Synergistic benefit targeting IKKe and IFNß in inflammatory arthritis. Ann Rheum Dis, 68:257-63, 2009. PMID: 18653628
  7. Svensson CI, Inoue T, Hammaker D, Fukushima A, Papa S, Franzoso G, Schett G, Corr M, Boyle DL, Firestein GS. Gadd45beta deficiency in rheumatoid arthritis: enhanced synovitis through JNK signaling. Arthritis Rheum. 60:3229-40, 2009. PMID: 19877043
  8. Yoshizawa T, Hammaker D, Boyle DL, Corr M, Flavell R, Davis R, Schett G, and Firestein GS. Role of MAPK kinase 6 in arthritis: distinct mechanism of action in inflammation and cytokine expression. J Immunol. 183:1360-7, 2009. PMID: 19561096
  9. Sweeney SE, Howard T, and Firestein GS. Synoviocyte innate immune responses: II. Regulation of interferon response genes by IRF3. J Immunol. 184:7162-8, 2010. PMCID: 20483755
  10. Fukushima A, Boyle DL, Corr M, Firestein GS. Kinetic analysis of synovial signaling and gene expression in animal models of arthritis. Ann Rheum Dis. 69:918-23, 2010. PMID: 19473996
  11. Guma M, Kashiwakura J, Crain B, Kawakami Y, Beutler B, Firestein GS, Kawakami T, Karin M, and Corr M. JNK1 controls mast cell degranulation and IL-1{beta} production in inflammatory arthritis. Proc Natl Acad Sci USA. 107:22122-7, 2010. PMID: 2113522
  12. Luo Y, Boyle DL, Hammaker D, Edgar M, Franzoso G, and Firestein GS. Suppression of collagen-induced arthritis in growth arrest and DNA damage inducible 45β (Gadd45β)-deficient mice. Arthritis Rheum. 63:2949-55, 2011. PMID: 21702006
  13. Bartok B, Boyle DL, Liu Y, Ren P, Ball ST, Bugbee WD, Rommel C, Firestein GS. PI3 Kinase δ Is a key regulator of synoviocyte function in rheumatoid arthritis. Am J Pathol. 43:173-85, 2012. PMID: 22433439
  14. Nakano K, Whitaker JW, Boyle DL, Wang W, Firestein GS. DNA methylome signature of rheumatoid arthritis synoviocytes. Ann Rheum Dis. 2013; 72:110-7. PMID: 22353730
  15. Nakano K, Boyle DL, Firestein GS. Regulation of DNA methylation in rheumatoid arthritis synoviocytes. J Immunol. 2013;190:1297-303. PMID: 23277489

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