Kn. Kose et al., PRO-INFLAMMATORY CYTOKINES DOWN-REGULATE PLATELET-DERIVED GROWTH-FACTOR-ALPHA RECEPTOR GENE-EXPRESSION IN HUMAN OSTEOBLASTIC CELLS, Journal of cellular physiology, 166(1), 1996, pp. 188-197
Platelet derived growth factor (PDGF) is thought to play a significant
role in bone repair and regeneration. We previously demonstrated that
PDGF-AA binding can be modulated by interleukin-l (IL-l). We now repo
rt that TNF-alpha significantly reduces PDGF-AA binding by decreasing
the number of PDGF-alpha receptor subunits on the surface of normal hu
man osteoblastic cells. This inhibition is likely due to a decrease in
synthesis of PDGF-alpha receptors since TNF-alpha causes a relatively
rapid decrease in PDGF-alpha receptor mRNA levels as determined by No
rthern blot analysis. The physiologic importance of this inhibition is
demonstrated by a TNF-alpha induced decrease in PDGF-AA stimulated ty
rosine kinase activity. When saturating concentrations of TNF-alpha we
re used, the addition of IL-l further inhibited PDGF-AA binding and fu
rther decreased surface expression of PDGF-alpha receptors. In contras
t, other mediators such as IL-6, PTH, 1,25(OH)(2) vit D-3, hydrocortis
one, PGE(2), bFGF, and IGF-1 had no effect. These results suggest that
binding to the PDGF-alpha receptor is decreased by the strong pro-inf
lammatory cytokines such as IL-1 beta and TNF-alpha rather than as a g
eneral response to mediators important in bone resorption or bone form
ation. TNF-alpha and IL-l are often co-expressed during destructive in
flammatory processes. Thus, TNF-alpha and IL-l may work in concert to
limit the response of osteoblastic cells to PDGF-AA during periods of
osseous inflammation. (C) 1996 Wiley-Liss, Inc.