Peroxisome proliferator-activated receptor gamma (
PPARgamma) is a
nuclear receptor involved in the regulation of many cellular processes. We and others have previously shown that
PPARgamma activators display anti-inflammatory and chondroprotective properties in vitro and improve the
clinical course and histopathological features in an experimental animal model of
osteoarthritis (OA). However, the expression and regulation of
PPARgamma expression in cartilage are poorly defined. This study was undertaken to investigate the quantitative expression and distribution of
PPARgamma in normal and OA cartilage and to evaluate the effect of IL-1beta, a prominent
cytokine in OA, on
PPARgamma expression in cultured chondrocytes. Immunohistochemical analysis revealed that the levels of
PPARgamma protein expression were significantly lower in OA cartilage than in normal cartilage. Using real-time RT-PCR, we demonstrated that PPARgamma1
mRNA levels were about 10-fold higher than
PPARgamma2 mRNA levels, and that only PPARgamma1 was differentially expressed: its levels in OA cartilage was 2.4-fold lower than in normal cartilage (p < 0.001).
IL-1 treatment of OA chondrocytes downregulated PPARgamma1 expression in a dose- and time-dependent manner. This effect probably occurred at the transcriptional level, because
IL-1 decreases both PPARgamma1
mRNA expression and PPARgamma1 promoter activity.
TNF-alpha,
IL-17, and
prostaglandin E2 (
PGE2), which are involved in the pathogenesis of OA, also downregulated PPARgamma1 expression. Specific inhibitors of the
mitogen-activated protein kinases (MAPKs) p38 (
SB203580) and
c-Jun N-terminal kinase (
SP600125), but not of
extracellular signal-regulated kinase (
PD98059), prevented IL-1-induced downregulation of PPARgamma1 expression. Similarly, inhibitors of
NF-kappaB signaling (
pyrrolidine dithiocarbamate,
MG-132, and SN-50) abolished the suppressive effect of
IL-1. Thus, our study demonstrated that PPARgamma1 is downregulated in OA cartilage. The pro-inflammatory
cytokine IL-1 may be responsible for this downregulation via a mechanism involving activation of the MAPKs (p38 and JNK) and
NF-kappaB signaling pathways. The IL-1-induced downregulation of
PPARgamma expression might be a new and additional important process by which
IL-1 promotes articular
inflammation and cartilage degradation.