Phosphoinositide 3-kinase δ regulates migration and invasion of synoviocytes in rheumatoid arthritis.
Cartilage destruction mediated by invasive fibroblast-like synoviocytes (FLS) plays a central role in pathogenesis of rheumatoid arthritis (RA). Increased cell migration and degradation of extracellular matrix are fundamental to these processes. The class I PI3Ks control cell survival, proliferation, and migration, which might be involved in cartilage damage in RA. PI3Kδ isoform was recently identified as a key regulator of FLS growth and survival, suggesting that it could contribute to synoviocyte aggressive behavior. Therefore, we assessed the role of PI3Kδ in RA synoviocyte migration and invasion. We observed that PI3Kδ inhibition or small interfering RNA knockdown decreased platelet-derived growth factor (PDGF)-mediated migration and invasion of FLS. We then showed that PI3Kδ regulates the organization of actin cytoskeleton and lamellipodium formation during PDGF stimulation. To gain insight into molecular mechanisms, we examined the effect of PI3Kδ inhibition on Rac1/PAK, FAK, and JNK activation. Our studies suggest that Rac1/PAK is key target of PDGF-mediated PI3Kδ signaling, whereas FAK and JNK are not involved. Thus, PI3Kδ contributes to multiple aspects of the pathogenic FLS behavior in RA. These observations, together with previous findings that PI3Kδ regulates FLS growth and survival, suggest that PI3Kδ inhibition could be chondroprotective in RA by modulating synoviocyte growth, migration, and invasion.
Division of Rheumatology, Allergy, and Immunology, University of California San Diego School of Medicine, La Jolla, CA 92093.
Beatrix
B
Bartok
Deepa
D
Hammaker
Gary S
GS
Firestein
D008841:Actin Cytoskeleton / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000276:immunology; D011554:Pseudopodia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013583:Synovial Membrane / Q000276:immunology* / Q000473:pathology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000276:immunology
D010982:Platelet-Derived Growth Factor; C107953:RAC1 protein, human; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D048670:MAP Kinase Kinase 4; D020830:rac1 GTP-Binding Protein