Esculetin suppresses proteoglycan metabolism by inhibiting the production of matrix metalloproteinases in rabbit chondrocytes.
The possible mechanism of the chondroprotective effect of 6,7-dihydroxycoumarin (esculetin) was investigated using primary cultures of rabbit articular chondrocytes. Esculetin (EST) significantly suppressed the proteoglycan depletion and the release of pulse-labeled [35S]proteoglycan from the matrix layer of rabbit chondrocytes treated with recombinant human interleukin-1alpha. The matrix metalloproteinase inhibitor, 1,10-phenanthroline, also blocked the proteoglycan depletion and [35S]proteoglycan release. From these results, it is likely that recombinant human interleukin-1alpha-induced proteoglycan depletion is mediated by matrix metalloproteinases. Although esculetin did not directly inhibit collagenolytic activity in the culture media, it significantly suppressed the production of pro-matrix metalloproteinase-1/interstitial procollagenase and pro-matrix metalloproteinase-3/prostromelysin 1, accompanied by a decrease in the steady-state levels of their mRNAs. These results suggest that esculetin is a therapeutically effective candidate for inhibition of cartilage destruction in osteoarthritis and rheumatoid arthritis.
Watanabe
K
K
Biomedical Research Laboratories, Kureha Chemical Industry, Tokyo, Japan.
Ito
A
A
Sato
T
T
Saito
T
T
Hayashi
H
H
Niitani
Y
Y
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D018929:Cell Culture Techniques; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D017364:Collagenases / Q000096:biosynthesis; D004347:Drug Interactions; D004792:Enzyme Precursors / Q000096:biosynthesis; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007596:Joints / Q000502:physiology*; D007717:Knee / Q000502:physiology; D008297:Male; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D010618:Phenanthrolines / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011509:Proteoglycans / Q000187:drug effects / Q000378:metabolism*; D012313:RNA / Q000302:isolation & purification; D011817:Rabbits; D012782:Shoulder / Q000502:physiology; D014468:Umbelliferones / Q000494:pharmacology*
D000975:Antioxidants; D004792:Enzyme Precursors; D007375:Interleukin-1; D010618:Phenanthrolines; D011480:Protease Inhibitors; D011509:Proteoglycans; D014468:Umbelliferones; D012313:RNA; D017364:Collagenases; D008666:Metalloendopeptidases; C022440:procollagenase; C048047:prostromelysin; C007628:esculetin; C025205:1,10-phenanthroline