Survivin is an essential mediator of arthritis interacting with urokinase signalling.
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.
Baran
Marcin
M
Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg, Sweden.
Möllers
Linda Nilsson
LN
Andersson
Sofia
S
Jonsson
Ing-Marie
IM
Ekwall
Anna-Karin Hultgård
AK
Bjersing
Jan
J
Tarkowski
Andrej
A
Bokarewa
Maria
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001168:Arthritis / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D015398:Signal Transduction; D000077022:Survivin; D013583:Synovial Membrane / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D051034:Inhibitor of Apoptosis Proteins; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D055293:Receptors, Urokinase Plasminogen Activator; D000077022:Survivin; D014568:Urokinase-Type Plasminogen Activator; C107489:BIRC5 protein, human; C000715470:MAS1 protein, human; C524898:PLAUR protein, human