Peroxisome proliferator-activated receptor ? activators inhibit interleukin-1?-induced nitric oxide and matrix metalloproteinase 13 production in human chondrocytes

Abstract

Objective To determine the effects of peroxisome proliferator–activated receptor γ (PPARγ) agonists on interleukin‐1 (IL‐1) induction of nitric oxide (NO) and matrix metalloproteinase 13 (MMP‐13) in human chondrocytes. Methods PPARγ expression and synthesis in human chondrocytes were determined by reverse transcriptase–polymerase chain reaction (RT‐PCR) and immunohistochemistry, respectively. Chondrocytes were cultured with IL‐1β, tumor necrosis factor α (TNFα), and IL‐17 in the presence or absence of PPARγ agonists, and NO and MMP‐13 synthesis and expression levels were measured. Transient transfection experiments were performed with the 7‐kb inducible NO synthase (iNOS) and 1.6‐kb MMP‐13 human promoters, as well as with the PPARγ expression vector and the activator protein 1 (AP‐1) and nuclear factor κB (NF‐κB) reporter constructs. Results RT‐PCR and immunohistochemical analysis revealed that human chondrocytes expressed and produced PPARγ. Treatment of chondrocytes with PPARγ ligands BRL 49653 and 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2), but not with PPARα ligand Wy 14643, decreased IL‐1β–induced NO and MMP‐13 production in a dose‐dependent manner. In addition, both iNOS and MMP‐13 messenger RNA were inhibited in the presence of 15d‐PGJ2. The inhibitory effect of PPARγ activation was not restricted to IL‐1β, since TNFα‐ and IL‐17–induced NO and MMP‐13 production were also inhibited by 15d‐PGJ2. In transient transfection experiments, we showed that a constitutively active form of mitogen‐activated protein kinase kinase kinase 1 (ΔMEKK‐1) induced the MMP‐13 and iNOS human promoter activity. This process was reduced by 15d‐PGJ2 and further inhibited by cotransfection with a PPARγ expression vector. Similarly, in a PPARγ‐dependent manner, 15d‐PGJ2 inhibited ΔMEKK‐1–induced AP‐1– and NF‐κB–luciferase reporter plasmid activation. Conclusion The findings of this study demonstrate that PPARγ agonists inhibit IL‐1β induction of both NO and MMP‐13 in human chondrocytes. The inhibition occurs at least at the transcriptional level through a PPARγ‐dependent pathway, probably by interfering with the activation of AP‐1 and NF‐κB.

The peroxisome proliferator–activated receptor γ agonist pioglitazone reduces the development of cartilage lesions in an experimental dog model of osteoarthritis: In vivo protective effects mediated through the inhibition of key signaling and catabolic pathways

“…More specifically, with regard to the pathophysiologic mechanisms of arthritis, studies have demonstrated that the activation of PPAR␥ could inhibit a number of important pathways responsible for the structural changes that occur during OA. For instance, PPAR␥ agonists were found to inhibit production of IL-1␤, NO, and MMP-13 in vitro in human OA chondrocytes (15,17), and to inhibit MMP-1 and IL-1␤ in human arthritis synovial fibroblasts (16,30). The inhibition of MMP-1 production was found to be associated with a reduction in activator protein 1 (AP-1) binding activity (16).…”

“…PPAR␥ agonists have been shown to be potent inhibitors of the synthesis of inflammatory cytokines, such as IL-1␤, TNF␣, and IL-6, by monocyte/ macrophage cells and other cell types (18,40). The effects of pioglitazone in terms of reducing the synthesis of the MMPs, including MMP-1, could be attributed to multiple mechanisms (15,16). The reduction in the activity of both the p38 and the ERK-1/2 pathways is likely to be a very important mechanism, since these pathways are predominant in the regulation of expression of MMP-1 in chondrocytes (17,21,42).…”

“…In recent years, the family of nuclear receptors, including peroxisome proliferatoractivated receptor ␥ (PPAR␥), has generated particular interest because of its potential role in regulating the synthesis of a large number of catabolic factors involved in arthritis. Several studies have demonstrated that the activation of PPAR␥ by natural ligands can reduce the expression and synthesis of those catabolic and inflammatory factors that have the most relevant role in diseases such as OA (15)(16)(17). These factors include inflammatory cytokines such as interleukin-1␤ (IL-1␤), tumor necrosis factor ␣ (TNF␣), and IL-6 (18), MMPs such as MMP-1 and MMP-13 (15,16), and NO (17).…”

“…Several studies have demonstrated that the activation of PPAR␥ by natural ligands can reduce the expression and synthesis of those catabolic and inflammatory factors that have the most relevant role in diseases such as OA (15)(16)(17). These factors include inflammatory cytokines such as interleukin-1␤ (IL-1␤), tumor necrosis factor ␣ (TNF␣), and IL-6 (18), MMPs such as MMP-1 and MMP-13 (15,16), and NO (17). This action of the PPAR␥ agonists is mediated through the inhibition of a number of signaling pathways, including the NF-B and MAPK pathways (17,18).…”

Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis

“…PPARG2 activation prevents the expression of several inflammatory genes responsible for the pathogenesis of OA, including interleukin-1β, inducible nitric acid synthase, cyclo-oxygenase-2 and microsomal prostaglandin-E2 synthase-1 4–7. There is also some evidence to suggest that PPARG2 activation may be chondroprotective by negatively regulating the expression of matrix metalloproteinase-1 and matrix metalloproteinase-13 and by preventing proteoglycan degradation 4589. It has also been shown that treatment with a PPARG2 activator, pioglitazone, shows beneficial effects in an experimental model of OA 10.…”