Platelet-activating factor inhibits proteoglycan synthesis and enhances neutrophil-mediated proteoglycan degradation in cartilage explants.
OBJECTIVE
Platelet-activating factor (PAF), which stimulates the release of tissue-destructive enzymes and reactive oxygen metabolites from neutrophils, was investigated for its role in neutrophil-mediated cartilage breakdown.


METHODS
Bovine cartilage explants were incubated with or without human neutrophils, PAF, and other reagents. Cartilage damage was measured as either proteoglycan degradation (percent release of 35S-labeled proteoglycan from 35S-labeled cartilage) or inhibition of proteoglycan synthesis (rate of incorporation of 35S into proteoglycan).


RESULTS
PAF increased neutrophil-mediated proteoglycan degradation in the 2-20 microM range. Three specific PAF-receptor antagonists, WEB2086, CV3988, and CV6209, reversed this effect of PAF. These antagonists also reduced the enhancement of neutrophil-mediated cartilage damage caused by granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF alpha). The results suggest that there may be a positive feedback mechanism whereby cytokine-primed neutrophils produce PAF, which amplifies the release of other tissue-damaging substances from neutrophils. In the absence of neutrophils, PAF (2-20 microM) inhibited the synthesis of proteoglycan by bovine cartilage. Neutrophils also inhibit proteoglycan synthesis, but PAF probably is not involved in this effect of neutrophils because the PAF receptor antagonists had no consistent effect.


CONCLUSIONS
PAF increases neutrophil-mediated cartilage proteoglycan degradation in vitro. GM-CSF and TNF alpha enhancement of neutrophil damage to cartilage is partly due to PAF. PAF alone inhibits cartilage proteoglycan synthesis.
Kowanko
I C
IC
Department of Immunology, Adelaide Children's Hospital, Australia.
Bates
E J
EJ
Ferrante
A
A
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D002417:Cattle; D002478:Cells, Cultured; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology*; D010742:Phospholipid Ethers / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins; D011509:Proteoglycans / Q000378:metabolism*; D011726:Pyridinium Compounds / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled; D013462:Sulfur Radioisotopes; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D001381:Azepines; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011509:Proteoglycans; D011726:Pyridinium Compounds; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013462:Sulfur Radioisotopes; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C039351:platelet activating factor receptor; C053321:CV 6209; C052518:WEB 2086; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C037913:CV 3988