Extended report
Esculetin inhibits cartilage resorption induced by interleukin
1
in combination with oncostatin M
S Elliott, A D Rowan, S Carrère, P Koshy, J B Catterall, T E Cawston
Department of
Rheumatology, Cookson Building, Medical School, Newcastle-upon-Tyne
NE2 4HH, UK
Correspondence to: Dr Elliott s.f.elliott{at}ncl.ac.uk
Accepted for publication 31 July 2000
OBJECTIVE
To determine
if a new inhibitor, esculetin (EST), can block resorption of cartilage.
METHODSInterleukin
1
(IL1, 0.04-5 ng/ml) and oncostatin M (OSM, 0.4-50 ng/ml) were
used to stimulate the release of proteoglycan and collagen from bovine
nasal cartilage and human articular cartilage in explant culture.
Proteoglycan and collagen loss were assessed by dimethylmethylene blue
and hydroxyproline assays, respectively. Collagenase levels were
measured by assay of bioactivity and by enzyme linked immunosorbent
assay (ELISA). The effects of EST on the expression of matrix
metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1
(TIMP-1) in the transformed human chondrocyte cell line T/C28a4 were
assessed by northern blot analysis. TIMP-1 protein levels were assayed
by ELISA. The effect of EST on the MMP-1 promoter was assessed using a
promoter-luciferase construct in transient transfection studies.
RESULTSEST inhibited
proteoglycan and collagen resorption in a dose dependent manner with
significant decreases seen at 66 µM and 100 µM EST, respectively.
Collagenolytic activity was significantly decreased in bovine nasal
cartilage cultures. In human articular cartilage, EST also inhibited
IL1 + OSM stimulated resorption and decreased MMP-1 levels. TIMP-1
levels were not altered compared with controls. In T/C28a4 chondrocytes
the IL1 + OSM induced expression of MMP-1, MMP-3, and MMP-13 mRNA
was reduced to control levels by 250 µM EST. TIMP-1 mRNA levels were
unaffected by EST treatment. All cytokine stimulation of an MMP-1
luciferase-promoter construct was lost in the presence of the inhibitor.
CONCLUSIONEST
inhibits degradation of bovine nasal cartilage and human articular
cartilage stimulated to resorb with IL1 + OSM.
© 2001 by Annals of the Rheumatic Diseases
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This article has been cited by other articles:
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Wahl, A F, Wallace, P M
(2001). Oncostatin M in the anti-inflammatory response. Ann Rheum Dis
60: iii75-80
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