Survivin is an essential mediator of arthritis interacting with urokinase signalling

Abstract

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.

Survivin but not Fms-like tyrosine kinase 3 ligand is up-regulated before the onset of rheumatoid arthritis: a pilot study

“…High levels of survivin were also detected in the rheumatoid synovia where the expression of survivin correlated with the synovial infiltration with macrophages and memory T cells and with the low rate of apoptosis. These findings suggested a key function for survivin in the regulation of invasive properties of fibroblasts in the inflamed rheumatic joint [24-26]. The result of our study is not consistent with these findings, since the concentration of survivin was increased before the patients presented any symptoms of joint disease.…”

Increased Extracellular Survivin in the Synovial Fluid of Rheumatoid Arthritis Patients: Fibroblast-like Synoviocytes as a Potential Source of Extracellular Survivin

“…Considering that increased cell proliferation and resistance to apoptosis contribute to increased numbers of FLS and chronic inflammatory cells in rheumatoid joints [18], survivin has important implications for the pathogenesis of RA. It has been reported that survivin may be an essential invasive mediator in RA through urokinase [19]. Survivin and xIAP are expressed in active rheumatoid synovium, suggesting the inhibition of apoptosis in RA cells [20].…”

The blocking of uPAR suppresses lipopolysaccharide-induced inflammatory osteoclastogenesis and the resultant bone loss through attenuation of integrin β3/Akt pathway

“…uPAR is expressed in multiple cells, such as monocytes, macrophages, T cells [18,19]. The uPAR expression is elevated during inflammation and tissue remodeling, and is associated with the development of inflammatory diseases, such as RA, periodontitis, cancer, and fibrosis [19][20][21][22][23][24][25]. uPAR also plays an important role in the regulation of bone homeostasis by influencing OB function and OC formation under non-inflammatory condition [26,27].…”