Background/Purpose:

Urokinase-type plasminogen activator receptor (uPAR), is a multi-functional receptor on cell surface, widely present in endothelial cells, fibroblasts, and a variety of malignant cells. Current studies have suggested that uPAR overexpressed on synovial tissues or in synovial fluid or plasma in patients with rheumatoid arthritis (RA). However, there are limited researches regarding the role of uPAR on fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLSs) and its underlying mechanisms. 

Methods: All synovial specimens were taken from patients, in which 8 patients with RA (met the 2009 ACR/EULAR criteria) , 4 patients with OA (consistent with 1995 ACR classification criteria) , and 3 patients with severe trauma who had , no other joint abnormalities or systemic disease. To study effects of uPAR on RA-FLSs, chemically synthesized small interference RNA(siRNA) specifically targeting the uPAR gene was transfected into RA-FLS by cationic liposome. Western blot and ELISA were taken to test inhibition efficiency. The proliferative inhibition rate was examined by the CCK8 assay. Flow cytometry was used to determine the change of cell cycle distribution and apoptosis. The migration and invasion ability of RA-FLSs were examined by a transwell assay. Western blot was performed to detect the influence of uPAR on the PI3K/Akt signaling pathway.Migration and tubule formation assays were used to explore the influence of RA-FLSs uPAR on angiogenesis.

Results:  Our studies show that the expression of uPAR protein was significantly higher in FLSs from RA than those from OA or traumatic injury patients. uPAR-siRNA could effectively block the uPAR expression of mRNA, protein level in RA-FLSs and soluble uPAR secretion in cell supernatant. uPAR gene silencing inhibited RA-FLSs proliferation by (28.62 ± 4.82)% at 72h, restrained cell transformation from the G0/G1 phase to S phase obviously, reduced RA-FLSs cell migration by (74.82 ± 2.16)% and invasion by (74.51 ± 4.73)% , and interfered with activation of the PI3K/Akt signaling pathway significantly. Cell supernatants from uPAR gene-silenced RA-FLSs markedly inhibited the migration and tubule formation ability of HUVEC (human umbilical vein endothelial cell ) (P <0.05).

Conclusion:

uPAR changes the biological characteristics of RA-FLSs and affects neoangiogenesis of synovial tissues in patients with RA, which may be associated with PI3K/Akt signaling pathway. These results imply that targeting of uPAR and its downstream signal pathway may provide beneficial therapeutic effects in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/upar-promotes-tumor-like-biologic-role-of-fibroblast-like-synoviocytes-through-pi3kakt-signaling-pathway-in-patients-with-rheumatoid-arthritis/