Pro-inflammatory cytokines downregulate platelet derived growth factor-alpha receptor gene expression in human...

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-1 (IL-1). We now report that TNF-alpha significantly reduces PDGF-AA binding by decreasing the number of PDGF-alpha receptor subunits on the surface of normal human 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 Northern blot analysis. The physiologic importance of this inhibition is demonstrated by a TNF-alpha induced decrease in PDGF-AA stimulated tyrosine kinase activity. When saturating concentrations of TNF-alpha were used, the addition of IL-1 further inhibited PDGF-AA binding and further decreased surface expression of PDGF-alpha receptors. In contrast, other mediators such as IL-6, PTH, 1,25(OH)2 vit D3, hydrocortisone, PGE2, bFGF, and IGF-1 had no effect. These results suggest that binding to the PDGF-alpha receptor is decreased by the strong pro-inflammatory cytokines such as IL-1 beta and TNF-alpha rather than as a general response to mediators important in bone resorption or bone formation. TNF-alpha and IL-1 are often co-expressed during destructive inflammatory processes. Thus, TNF-alpha and IL-1 may work in concert to limit the response of osteoblastic cells to PDGF-AA during periods of osseous inflammation.