title: Focal adhesion kinase is required for synovial fibroblast invasion, but not murine inflammatory arthritis.
abstract: BACKGROUND
  Synovial fibroblasts invade cartilage and bone, leading to joint destruction in rheumatoid arthritis. However, the mechanisms that regulate synovial fibroblast invasion are not well understood. Focal adhesion kinase (FAK) has been implicated in cellular invasion in several cell types, and FAK inhibitors are in clinical trials for cancer treatment. Little is known about the role of FAK in inflammatory arthritis, but, given its expression in synovial tissue, its known role in invasion in other cells and the potential clinical availability of FAK inhibitors, it is important to determine if FAK contributes to synovial fibroblast invasion and inflammatory arthritis.
  
  
  METHODS
  After treatment with FAK inhibitors, invasiveness of human rheumatoid synovial fibroblasts was determined with Matrigel invasion chambers. Migration and focal matrix degradation, two components of cellular invasion, were assessed in FAK-inhibited rheumatoid synovial fibroblasts by transwell assay and microscopic examination of fluorescent gelatin degradation, respectively. Using mice with tumor necrosis factor α (TNFα)-induced arthritis in which fak could be inducibly deleted, invasion and migration by FAK-deficient murine arthritic synovial fibroblasts were determined as described above and arthritis was clinically and pathologically scored in FAK-deficient mice.
  
  
  RESULTS
  Inhibition of FAK in human rheumatoid synovial fibroblasts impaired cellular invasion and migration. Focal matrix degradation occurred both centrally and at focal adhesions, the latter being a novel site for matrix degradation in synovial fibroblasts, but degradation was unaltered with FAK inhibitors. Loss of FAK reduced invasion in murine arthritic synovial fibroblasts, but not migration or TNFα-induced arthritis severity and joint erosions.
  
  
  CONCLUSIONS
  FAK inhibitors reduce synovial fibroblast invasion and migration, but synovial fibroblast migration and TNFα-induced arthritis do not rely on FAK itself. Thus, inhibition of FAK alone is unlikely to be sufficient to treat inflammatory arthritis, but current drugs that inhibit FAK may inhibit multiple factors, which could increase their efficacy in rheumatoid arthritis.
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Shelef
authors.forename: David A
authors.initials: DA
authors.lastname: Bennin
authors.forename: Nihad
authors.initials: N
authors.lastname: Yasmin
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Warner
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Hilary E
authors.initials: HE
authors.lastname: Beggs
authors.forename: Anna
authors.initials: A
authors.lastname: Huttenlocher
mesh_terms: D000818:Animals; D001168:Arthritis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000473:pathology; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D015363:Quinolones / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: C521108:6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one; D007211:Indoles; C527797:N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide; D015363:Quinolones; D013449:Sulfonamides; D013450:Sulfones; D051416:Focal Adhesion Protein-Tyrosine Kinases