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Department of Medicine, Arthritis Center, Boston University School of Medicine, Boston, MA 02118
Growth of and metalloproteinase production by fibroblast-like
synoviocytes (FLSs) in patients with rheumatoid arthritis (RA)
contribute to cartilage and bone destruction associated with
development of the expanding inflammatory tissue referred to as pannus.
Increased levels of extracellular matrix (ECM) proteins in the pannus
suggest that intracellular signals generated through integrin receptors
might control these processes. We developed a cell culture system
permitting accurate assessment of the effect of cell adhesion to
various ECM proteins on FLS phenotype. We show that FLS proliferation
to platelet-derived growth factor requires a second signal provided by
adhesion to an ECM protein. Fibronectin, vitronectin, collagen, or
laminin could provide the second signal and was similarly required for
the proliferation of FLSs from RA or osteoarthritis patients. Adhesion
to fibronectin, collagen, or Arg-Gly-Asp peptide down-regulated
collagenase expression. Primarily
v integrin receptors
mediated this down-regulation upon adhesion to fibronectin. Loss of
cell adhesion and TNF-
stimulation synergistically increased
collagenase expression. Increased collagenase expression upon
nonadherence was mimicked by treatment with cytochalasin B, suggesting
that the loss of cytoskeletal structure associated with a change in
cell shape mediates increased collagenase in nonadherent cells. Thus,
although increased fibronectin in the lining layer in RA might be
expected to inhibit collagenase expression, the change in cell shape
associated with this multilayer structure might actually lead to
increased collagenase expression.
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