Molecular basis of anti-inflammatory action of platelet-rich plasma on human chondrocytes: mechanisms of NF-κB inhibition via HGF.
Loss of articular cartilage through injury or disease presents major clinical challenges also because cartilage has very poor regenerative capacity, giving rise to the development of biological approaches. As autologous blood product, platelet-rich plasma (PRP) provides a promising alternative to surgery by promoting safe and natural healing. Here we tested the possibility that PRP might be effective as an anti-inflammatory agent, providing an attractive basis for regeneration of articular cartilage, and two principal observations were done. First, activated PRP in chondrocytes reduced the transactivating activity of NF-κB, critical regulator of the inflammatory process, and decreased the expression of COX-2 and CXCR4 target genes. By analyzing a panel of cytokines with different biological significance, in activated PRP we observed increases in hepatocyte growth factor (HGF), interleukin-4 and tumor necrosis factor-α (TNF-α). HGF and TNF-α, by disrupting NF-κB-transactivating activity, were important for the anti-inflammatory function of activated PRP. The key molecular mechanisms involved in PRP-inhibitory effects on NF-κB activity were for HGF the enhanced cellular IkBα expression, that contributed to NF-κB-p65 subunit retention in the cytosol and nucleo-cytoplasmic shuttling, and for TNF-α the p50/50 DNA-binding causing inhibition of target-gene expression. Second, activated PRP in U937-monocytic cells reduced chemotaxis by inhibiting chemokine transactivation and CXCR4-receptor expression, thus possibly controlling local inflammation in cartilage. In conclusion, activated PRP is a promising biological therapeutic agent, as a scaffold in micro-invasive articular cartilage regeneration, not only for its content of proliferative/differentiative growth factors, but also for the presence of anti-inflammatory agents including HGF.
Bendinelli
Paola
P
Dipartimento di Morfologia Umana e Scienze Biomediche Città Studi, Molecular and Clinical Pathology Laboratories, Università degli Studi di Milano, Milano, Italy.
Matteucci
Emanuela
E
Dogliotti
Giada
G
Corsi
Massimiliano M
MM
Banfi
Giuseppe
G
Maroni
Paola
P
Desiderio
Maria Alfonsina
MA
D021581:Active Transport, Cell Nucleus; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis; D019902:Chondrocytes / Q000276:immunology / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000097:blood*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D010766:Phosphorylation; D017713:Platelet Transfusion; D019718:Receptors, CXCR4 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D020298:U937 Cells
C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C066855:HGF protein, human; D020672:I-kappa B Proteins; C508598:IL4 protein, human; D018836:Inflammation Mediators; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C000606204:NFKBIA protein, human; C498143:RELA protein, human; D019718:Receptors, CXCR4; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D015847:Interleukin-4; D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human