Tyrosine kinase signal transduction in rheumatoid synovitis.
Explants of synovial cells in rheumatoid arthritis display a transformed phenotype with focus formation and anchorage-independent growth. Many of the cytokines that activate these fibroblasts mediate their action through tyrosine kinase growth factor receptors. Mechanisms of signal transduction via such tyrosine kinases are therefore relevant to the pathogenesis of rheumatoid lesions. Data are presented using the neu oncogene product p185neu as a model system to explore signal transduction by receptor tyrosine kinases. Evidence is shown that increased tyrosine kinase activity in the oncogenic form of this protein may result from dimerization of the tyrosine kinase receptor. In the normal cellular counterpart of p185neu, dimerization appears to be mediated by the action of an as yet unidentified ligand. Dimerization also appears to be important in signal transduction mediated by epidermal growth factor, platelet-derived growth factor, and colony-stimulating factor 1. These cytokines also alter the phenotype of rheumatoid synovial fibroblasts to resemble transformed fibroblasts. Additionally, preliminary data that suggest increased tyrosine kinase activity in rheumatoid arthritis synovia compared with osteoarthritis synovia are presented. Molecular characterization of tyrosine kinase receptors will be an important direction for future studies of the pathogenesis of rheumatoid disease.
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia.
W V
WV
Williams
J M
JM
VonFeldt
T
T
Ramanujam
D B
DB
Weiner
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000201:enzymology; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology / Q000648:ultrastructure; D051379:Mice; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D010003:Osteoarthritis / Q000201:enzymology; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface / Q000032:analysis / Q000737:chemistry / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D013585:Synovitis / Q000503:physiopathology*; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure
D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface