Multiple physiological and pathological processes as well as tissue
architecture in multicellular organisms is maintained or regulated by
adhesive interactions between cell-cell and cell-underlying extracellular
matrix. The relevance of interaction of cells with proteoglycans (PGs)
in matrix or on cell surface to cell signaling has been recently emerging.
We here document that PGs is involved in cell signaling, shedding light
upon inflammatory processes in rheumatoid arthritis (RA).
RA is a representative model of a persistent inflammatory process characterized
by marked infiltration of the synovium by T cells. Chemokines produced
in large amounts from inflamed tissues trigger integrin-mediated adhesion
of T cells to endothelial cells, which results in T cell accumulation
in the tissues. Endothelial cells in RA synovium characteristically
express heparan sulfate proteoglycan (HS-PG), some of which is CD44v3.
HS-PG on endothelium is involved in T cell integrin-triggering by "posting"
chemokines and by "relaying" them to their receptors on T cells without
being washed away by blood flow, which leads to efficient migration
of T cells.
RA synovitis is an extreme characteristic comprised of two diverse
phenomena of RA synovial cells, intractable proliferation and growth
arrest of the cells, and the mechanisms altering its balance lead to
the pathogenesis of RA. Hyaluronan (HA) is the major extracellular PG
found in matrix of RA synovium. RA synovial cells highly express CD44,
a major receptor for HA. Engagement of CD44 by HA augments Fas as well
as VCAM-1 on the cells, and CD44-mediated signaling is involved in adhesion
of synovial cells with T cells via VLA-4/VCAM-1 and subsequent interaction
of Fas/Fas-L pathway, resulting in synovial cell apoptosis.
We thereby propose that PG is involved in signaling indirectly or directly;
cell surface PG is involved in signaling to induce adhesion and migration
of T cells by binding chemokines; interaction with matrix PG transduces
signals to augment VCAM-1 and Fas on cell surface, which leads to apoptosis
of synovial cells. Thus, the role of PG is most relevant to inflammatory
processes such as rheumatoid synovitis.