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.
Sabatini
M
M
Division of Rheumatology, Institut de Recherches Servier (IdRS), 11 rue des Moulineaux, 92150 Suresnes, France. massimo.sabatini@fr.netgrs.com
Bardiot
A
A
Lesur
C
C
Moulharat
N
N
Thomas
M
M
Richard
I
I
Fradin
A
A
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