Inhibitors of hyaluronan export from hops prevent osteoarthritic reactions.
METHODS
An early reaction in osteoarthritic chondrocytes is hyaluronan overproduction followed by proteoglycan loss and collagen degradation. We recently found that hyaluronan is exported by the ATP-binding cassette transporter multidrug resistance associated protein 5 (MRP5) in competition with cGMP and that some phosphodiesterase 5 inhibitors also inhibited hyaluronan export. These inhibitors also prevented osteoarthritic reactions in cartilage. In an effort to identify the improved inhibitors directed primarily toward MRP5, we analyzed the flavonoids.


RESULTS
Prenylflavonoids from hop xanthohumol, isoxanthohumol and 8-prenylnaringenin inhibited MRP5 export at lower concentrations than phosphodiesterase 5 activity. They were analyzed for their effect on IL-induced osteoarthritic reactions in bovine chondrocytes. Xanthohumol was the superior compound to inhibit hyaluronan export, as well as proteoglycan and collagen loss. It also prevented the shedding of metalloproteases into the culture medium. It directly inhibited MRP5, because it reduced the export of the MRP5 substrate fluorescein immediately and did not influence the hyaluronan synthase activity.


CONCLUSIONS
Xanthohumol may be a natural compound to prevent hyaluronan overproduction and subsequent reactions in osteoarthritis.
Stracke
Dennis
D
Muenster University Hospital, Institute of Physiological Chemistry and Pathobiochemistry, Muenster, Germany.
Schulz
Tobias
T
Prehm
Peter
P
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D027582:Humulus / Q000737:chemistry; D006820:Hyaluronic Acid / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D011427:Propiophenones / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D003094:Collagen; D006152:Cyclic GMP; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D044950:Flavanones; D005419:Flavonoids; D006820:Hyaluronic Acid; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D058986:Phosphodiesterase 5 Inhibitors; D010936:Plant Extracts; D011427:Propiophenones; D011509:Proteoglycans; D044004:Xanthones; C119737:8-prenylnaringenin; C512910:isoxanthohumol; C104536:xanthohumol