The GTPase Rac regulates the proliferation and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients.
Fibroblast-like synoviocytes (FLS) isolated from joints of rheumatoid arthritis (RA) patients display proliferative and invasive properties reminiscent of those of malignant tumor cells. Rac small GTPases play an important role in tumor cell proliferation and invasion. We therefore investigated the potential role of Rac proteins in the proliferative and invasive behavior of RA-FLS. We showed that inhibiting Rac activity with the Rac-specific small molecule inhibitor NSC23766 causes a strong inhibition of RA-FLS proliferation, without affecting cell survival. Rac inhibition also results in a strong reduction in RA-FLS invasion through reconstituted extracellular matrix and a less marked inhibition of two-dimensional migration as measured by monolayer wound healing. We also showed that small interfering RNA-mediated depletion of Rac1 inhibits RA-FLS proliferation and invasion to a similar extent as NSC23766. These results demonstrate for the first time that Rac proteins play an important role in the aggressive behavior of FLS isolated from RA patients. In addition, we observed that inhibiting Rac proteins prevents JNK activation and that the JNK inhibitor SP600125 strongly inhibits RA-FLS invasion, suggesting that Rac-mediated JNK activation contributes to the role of Rac proteins in the invasive behavior of RA-FLS. In conclusion, Rac-controlled signaling pathways may present a new source of drug targets for therapeutic intervention in RA.
Chan
Amanda
A
Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, New York 11030, USA.
Akhtar
Mumtaz
M
Brenner
Max
M
Zheng
Yi
Y
Gulko
Percio S
PS
Symons
Marc
M
D000199:Actins / Q000378:metabolism; D000634:Aminoquinolines / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D013582:Synovial Fluid / Q000187:drug effects / Q000201:enzymology*; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000199:Actins; D000634:Aminoquinolines; C487513:NSC 23766; D011743:Pyrimidines; D034741:RNA, Small Interfering; D048031:JNK Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins