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From the Reid Rheumatology Laboratory, Division of Autoimmune Diseases and Transplantation, The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Victoria, Australia
Angiogenesis and synovial cell hyperplasia are characteristic
features of rheumatoid arthritis (RA). Many growth and survival factors
use receptors belonging to the tyrosine kinase family that share
conserved motifs within the intracellular catalytic domains. To
understand further the molecular basis of cellular hyperplasia in
RA, we have used degenerate primers based on these motifs and
RNA obtained from the synovium of a patient with RA to perform reverse
transcriptase-polymerase chain reaction. We report detection of the
receptor tyrosine kinase (RTK) Axl in RA synovium and we document the
expression pattern of Axl in capillary endothelium, in vascular
smooth muscle cells of arterioles and veins, and in a subset of
synovial cells in RA synovial tissue. Gas6 (for growth arrest-specific
gene 6), which is a ligand for Axl and is related to the
coagulation factor protein S, was found in synovial fluid and
tissue from patients with RA and osteoarthritis. Axl expression and
function was studied in human umbilical vein endothelial cells
(HUVECs). Gas6 bound to HUVECs; soluble Axl inhibited this binding.
Exogenous Gas6 protected HUVECs from apoptosis in response to
growth factor withdrawal and from TNF
-mediated cytotoxicity. These
findings may reveal a new aspect of vascular physiology, which
may also be relevant to formation and maintenance of the abnormal
vasculature in the rheumatoid synovium.
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