Inhibitors of hyaluronan export prevent proteoglycan loss from osteoarthritic cartilage.
OBJECTIVE
Osteoarthritis (OA) is characterized by cartilage erosion, proteolysis of aggrecan and collagen, and disturbed synthesis rates of aggrecan and hyaluronan by chondrocytes. The hypothesis is tested that hyaluronan overproduction contributes to aggrecan loss from osteoarthritic cartilage.


METHODS
Human chondrocytes or bovine cartilage explants were incubated with interleukin 1beta (IL-1beta) to induce upregulation of hyaluronan and downregulation of aggrecan. OA was induced by injection of iodoacetate into the synovial cavity in rat knees. Hyaluronan export was inhibited by ATP-binding cassette transporter inhibitors such as the multidrug resistance (MDR) inhibitors valspodar or verapamil. The concentration of aggrecan was measured in cell culture media or visualized histochemically in cartilage tissue sections.


RESULTS
Valspodar inhibited hyaluronan export from human chondrocytes in cell culture selectively without reducing aggrecan secretion. Valspodar and other MDR inhibitors prevented loss of aggrecan from osteoarthritic cartilage explants in culture. Verapamil prevented loss of aggrecan from cartilage in osteoarthritic rat knees.


CONCLUSIONS
Hyaluronan is synthesized at plasma membranes and exported out of the cell. We recently identified an ATP-binding cassette transport system that is responsible for hyaluronan export. A number of ATP-binding cassette transport inhibitors are known and are in use clinically. These inhibitors were used here to inhibit hyaluronan export and to prevent aggrecan loss from arthritic cartilage. New drugs for treatment of arthritis are suggested by these studies.
Prehm
Peter
P
Muenster University Hospital, Institute of Physiological Chemistry and Pathobiochemistry, Münster, Germany. prehm@uni-muenster.de
D053674:Aggrecans; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D002460:Cell Line; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006614:Hindlimb; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D007596:Joints / Q000187:drug effects / Q000473:pathology; D037181:Lectins, C-Type; D008297:Male; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
C508321:Acan protein, rat; D053674:Aggrecans; D003524:Cyclosporins; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D037181:Lectins, C-Type; D011509:Proteoglycans; D006820:Hyaluronic Acid; C070272:valspodar