title: Role of p21-activated kinase 1 in regulating the migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients.
abstract: OBJECTIVE
  To investigate the role of p21-activated kinase 1 (PAK1) in regulating migration, invasion and MMP expression in RA fibroblast-like synoviocytes (FLS).
  
  
  METHODS
  RA FLS migration and invasion in vitro were measured by the Boyden chamber method. Invasion of RA FLS into cartilage was detected in the severe combined immunodeficiency (SCID) mouse co-implantation model of RA in vivo. PAK1 and MT1-MMP expression were examined by western blotting. ELISA was used to measure the production and activity of MMPs.
  
  
  RESULTS
  Phosphorylated PAK1 (p-PAK1) protein expression was increased in ex vivo synovial membrane cells from RA patients. Stimulation with IL-1β or TNF-α up-regulated p-PAK1 expression. Inhibition of PAK1 by transfection with dominant negative PAK1 mutant (dnPAK1) reduced in vitro migration and invasion of RA FLS. In the SCID mouse model, RA FLS invasion into cartilage was attenuated by transfection with dnPAK1 in vivo. PAK1 regulated IL-1β-induced production and activity of MMP-13 and MT1-MMP. Inhibition of MMP-13 or MT1-MMP activity also reduced RA FLS invasion. Furthermore, dnPAK1 transfection inhibited c-Jun N-terminal kinase (JNK) activation, but did not affect the activities of extracellular signal-regulated kinases and p38. Inhibition of the JNK activity by chemical inhibitor significantly reduced the migration, invasion and production of MMP-13 and MT1-MMP.
  
  
  CONCLUSIONS
  PAK1 plays an important role in regulating the migration, invasion and production and activity of MMPs in RA FLS, which is mediated by the JNK pathway. This suggests a novel strategy targeting PAK1 to prevent joint destruction of RA.
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Di
authors.initials: D
authors.lastname: Fu
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Yang
authors.forename: Youjun
authors.initials: Y
authors.lastname: Xiao
authors.forename: Haobo
authors.initials: H
authors.lastname: Lin
authors.forename: Yujin
authors.initials: Y
authors.lastname: Ye
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Zhan
authors.forename: Liuqin
authors.initials: L
authors.lastname: Liang
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Yang
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Hanshi
authors.initials: H
authors.lastname: Xu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D015153:Blotting, Western; D002465:Cell Movement; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology*; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D013582:Synovial Fluid / Q000201:enzymology*; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology*; D054462:p21-Activated Kinases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004247:DNA; C515903:PAK1 protein, human; D054462:p21-Activated Kinases