PRO-INFLAMMATORY CYTOKINES DOWN-REGULATE PLATELET-DERIVED GROWTH-FACTOR-ALPHA RECEPTOR GENE-EXPRESSION IN HUMAN OSTEOBLASTIC CELLS

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.