Calcium pentosan polysulfate inhibits the catabolism of aggrecan in articular cartilage explant cultures.
OBJECTIVE
The catabolism of aggrecan and loss of aggrecan fragments from articular cartilage is a key event in the pathogenesis of arthritic diseases such as osteoarthritis. The catabolism of aggrecan is mediated by the specific proteolytic activity termed aggrecanase. The aim of this study was to investigate the effect of the chondroprotective agent calcium pentosan polysulfate (CaPPS) on the aggrecanase-mediated catabolism of aggrecan.


METHODS
The catabolism of 35S-labeled aggrecan and loss of tissue glycosaminoglycans (GAGs) were investigated using bovine articular cartilage explant cultures maintained in medium containing varying concentrations of CaPPS (1-100 microg/ml) in the presence or absence of 10(-6)M retinoic acid or 7 ng/ml recombinant human interleukin-1alpha (rHuIL-1alpha). In addition, the effect of CaPPS on the degradation of aggrecan monomers by aggrecanase activity present in conditioned medium from joint capsule explant cultures was investigated.


RESULTS
CaPPS inhibited the catabolism of 35S-labeled aggrecan in a dose-dependent manner, particularly when retinoic acid or rHuIL-1alpha was used to stimulate aggrecan catabolism. These effects were reflected in the tissue levels of GAG remaining in these cultures at the end of the experiment. CaPPS inhibited the degradation of aggrecan monomers by soluble aggrecanase activity.


CONCLUSIONS
CaPPS inhibits the catabolism of aggrecan by articular cartilage in a dose-dependent manner, particularly when the processes responsible for aggrecan loss are stimulated. This effect occurs, at least in part, through direct inhibition of aggrecanase activity. CaPPS did not adversely affect overall chondrocyte metabolism, as shown by the incorporation of 35S-sulfate and 3H-leucine into macromolecules and by lactate production in cartilage explant cultures.
Munteanu
S E
SE
La Trobe University, Bundoora, Victoria, Australia.
Ilic
M Z
MZ
Handley
C J
CJ
D053674:Aggrecans; D002358:Cartilage, Articular / Q000378:metabolism*; D003470:Culture Media; D017077:Culture Media, Conditioned; D010450:Endopeptidases / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007773:Lactates / Q000378:metabolism; D037181:Lectins, C-Type; D046911:Macromolecular Substances; D009924:Organ Culture Techniques; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology*; D011509:Proteoglycans / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013462:Sulfur Radioisotopes; D014212:Tretinoin / Q000494:pharmacology; D014316:Tritium
D053674:Aggrecans; D003470:Culture Media; D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D007773:Lactates; D037181:Lectins, C-Type; D046911:Macromolecular Substances; D011509:Proteoglycans; D011994:Recombinant Proteins; D013462:Sulfur Radioisotopes; D014316:Tritium; D010426:Pentosan Sulfuric Polyester; D014212:Tretinoin; D010450:Endopeptidases; C083641:aggrecanase