Focal adhesion kinase is required for synovial fibroblast invasion, but not murine inflammatory arthritis

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 inhibi...

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Published in:	Arthritis research & therapy Vol. 16; no. 5; p. 464
Main Authors:	Shelef, Miriam A, Bennin, David A, Yasmin, Nihad, Warner, Thomas F, Ludwig, Thomas, Beggs, Hilary E, Huttenlocher, Anna
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 04-10-2014 BioMed Central
Subjects:	Animals Antiarthritic agents Arthritis - enzymology Arthritis - genetics Arthritis - pathology Arthritis, Rheumatoid - enzymology Arthritis, Rheumatoid - pathology Blotting, Western Cancer Care and treatment Cell Movement - drug effects Cells, Cultured Fibroblasts - drug effects Fibroblasts - metabolism Fibroblasts - pathology Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors Focal Adhesion Protein-Tyrosine Kinases - genetics Focal Adhesion Protein-Tyrosine Kinases - metabolism Humans Indoles - pharmacology Mice, 129 Strain Mice, Inbred C57BL Mice, Transgenic Microscopy, Fluorescence Quinolones - pharmacology Sulfonamides - pharmacology Sulfones - pharmacology Synovial Membrane - metabolism Synovial Membrane - pathology Time Factors
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Summary:	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. 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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1478-6354 1478-6362 1478-6354
DOI:	10.1186/s13075-014-0464-6