Open AccessSurvivin is an essential mediator of arthritis interacting with urokinase signalling
Author(s) -
Baran Marcin,
Möllers Linda Nilsson,
Andersson Sofia,
Jonsson IngMarie,
Ekwall AnnaKarin Hultgård,
Bjersing Jan,
Tarkowski Andrej,
Bokarewa Maria
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00721.x
Subject(s) - survivin , urokinase receptor , cancer research , kinase , tyrosine kinase , signal transduction , gene silencing , oncogene , immunology , biology , receptor , microbiology and biotechnology , medicine , cell cycle , cell , cell culture , biochemistry , genetics , gene
Proto‐oncogene survivin has recently been identified as a prognostic marker distinguishing patients with destructive rheumatoid arthritis (RA). In the present material of 132 RA patients and 82 controls, the levels of survivin correlated to urokinase (uPA) ( r = 0.46), a plasminogen activator over‐expressed in inflamed joints and known to exhibit potent arthritogenic properties. Here we evaluate the functional relationship between these proteins using primary synovial fibroblasts and leucocytes of RA patients, human monocytic (THP‐1) and fibroblast (MRC‐5) cell lines. Using inhibitors of intracellular signalling, we show that uPA and survivin share common transduction pathways in synovial fibroblasts being dependent on the activity of tyrosine kinases, phosphatidylinositide 3 kinase and mitogen effector kinase. Moreover, uPA production is significantly reduced in fibroblasts if survivin synthesis has been silenced by siRNA. Importantly, silencing of survivin in fibroblasts prevented their invasive growth in knee joints of severe combined immune deficient mice. Interaction of uPA with receptor up‐regulates survivin expression in leucocytes. In turn, survivin is required for the up‐regulation of uPA receptor on the cell surface. These findings indicate that survivin is an essential mediator of arthritogenic properties of uPA regulating its synthesis in synovial fibroblasts and uPAR expression in leucocytes. Close correlation between survivin and uPA levels in patients with RA supports the importance of this connection for the pathogenesis of arthritis.