Effects of agonists of peroxisome proliferator-activated receptor gamma on proteoglycan degradation and matrix metalloproteinase production in rat cartilage in vitro.
OBJECTIVE
To examine the effects of agonists of peroxisome proliferator-activated receptor (PPAR) gamma on proteoglycan degradation induced by interleukin (IL)-1beta or tumor necrosis factor (TNF)alpha in cartilage in vitro.


METHODS
Proteoglycan degradation was measured as release of radioactivity from rat cartilage explants previously labeled with (35)SO2-4. Western blots were used to examine tissue levels of aggrecan neoepitopes NITEGE and VDIPEN, generated by aggrecanases and matrix metalloproteinases (MMP), respectively. Production of MMP-2, -3 and -9 by cultured rat chondrocytes was measured by zymography and by fluorimetric assay.


RESULTS
IL-1beta-induced proteoglycan degradation was likely due to aggrecanase, since it was associated with a strong increase of NITEGE signal. MMP-dependent VDIPEN signal increased only after further incubation with pro-MMP activator APMA. PPAR agonists 15d-PGJ(2) and GI262570 (10 microM) inhibited IL-1beta- and TNFalpha-induced proteoglycan degradation measured both before and after addition of APMA. The agonists also inhibited cytokine-induced MMP production by isolated chondrocytes.


CONCLUSIONS
This study shows that PPARgamma agonists inhibit cytokine-induced proteoglycan degradation mediated by both aggrecanase and MMP. This effect is associated with inhibition of production of MMP-3 and -9. These results support the interest for PPARgamma agonists as candidate inhibitors of pathological cartilage degradation.
Division of Rheumatology, Institut de Recherches Servier (IdRS), 11 rue des Moulineaux, 92150 Suresnes, France. massimo.sabatini@fr.netgrs.com
M
M
Sabatini
A
A
Bardiot
C
C
Lesur
N
N
Moulharat
M
M
Thomas
I
I
Richard
A
A
Fradin
D000818:Animals; D002356:Cartilage / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D005470:Fluorometry; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D011509:Proteoglycans / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D014157:Transcription Factors / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D011509:Proteoglycans; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D010450:Endopeptidases; D020782:Matrix Metalloproteinases; C083641:aggrecanase