Evidence for the Presence of Peroxisome Proliferator-activated Receptor (PPAR) α and γ and Retinoid Z Receptor in Cartilage

Abstract

Peroxisome proliferator-activated receptor (PPAR) ␣, PPAR␥, and retinoid acid receptor-related orphan receptor (ROR) ␣ are members of the nuclear receptor superfamily of ligand-activated transcription factors. Although they play a key role in adipocyte differentiation, lipid metabolism, or glucose homeostasis regulation, recent studies suggested that they might be involved in the inflammation control and especially in the modulation of the cytokine production. This strongly suggests that these transcriptional factors could modulate the deleterious effects of interleukin-1 (IL-1) on cartilage. However, to date, their presence in cartilage has never been investigated. By quantitative reverse transcription-polymerase chain reaction, Western blot, and immunocytochemistry analysis, we demonstrated, for the first time, the presence of PPAR␣, PPAR␥, and ROR␣ in rat cartilage, at both mRNA and protein levels. Comparatively, the PPAR␣ mRNA content in cartilage was much lower than in the liver but not significantly different to that of the adipose tissue. PPAR␥ mRNA expression in cartilage was weak, when compared with adipose tissue, but similar to that found in the liver. ROR␣ mRNA levels were similar in the three tissues. mRNA expression of the three nuclear receptors was very differently modulated by IL-1 or mono-iodoacetate treatments. This indicates that they should be unequally involved in the effects of IL-1 on chondrocyte, which is in accordance with results obtained in other cell types. Indeed, we showed that 15d-PGJ2 mainly, but also the drug troglitazone, that are ligands of PPAR␥ could significantly counteract the decrease in proteoglycan synthesis and NO production induced by IL-1. By contrast, PPAR␣ ligands such as Wy-14,643 or clofibrate had no effect on this process. Therefore, the presence of PPAR␥ in chondrocytes opens up new perspectives to modulate the effects of cytokines on cartilage by the use of specific ligands. The function of the two other transcription factors, PPAR␣ and ROR␣ identified in chondrocytes remains to be explored. Articular cartilage is a major component of the joint, and its mechanical properties depend on the integrity of the extracellular matrix, which is composed mainly of proteoglycans and collagens (1). Its progressive destruction, which results from an imbalance between the anabolic and catabolic processes, is a common feature of rheumatoid arthritis and osteoarthritis (OA).1 Interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣ (TNF␣) have been shown to inhibit the synthesis of cartilage components and to promote their degradation by activating metalloproteases (2, 3). Concurrently to these effects, they induce the production by chondrocytes of inflammatory mediators such as prostaglandins, nitric oxide (NO), and other reactive oxygen species (4). To date, most of the drugs marketed as nonsteroidal anti-inflammatory drugs or corticosteroids are unable to prevent cartilage damage (5). Thus, intense investigations are carried out to precise the transduction pathways that impair c...

Activation of the peroxisome proliferator–activated receptor α pathway potentiates interleukin‐1 receptor antagonist production in cytokine‐treated chondrocytes

“…Our findings are at variance with those of Bordji et al, who did not observe any effect of 500 M CloF on 35 S sulfate incorporation and nitrite production in rat chondrocytes in culture (20). This discrepancy could be explained either by interspecies differences in PPAR␣ ligand recognition as already described by others (21), or by the different experimental procedures used.…”

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

“…Within joints, several types of cells could support the antiinflammatory potency of PPAR␥ agonists, since this PPAR isotype is expressed constitutively in synoviocytes (24), macrophages (19), and chondrocytes (36). In addition, each cell type has pathophysiologic relevance to joint inflammation by their production of mediators of inflammation or matrix-degrading enzymes and can therefore be considered a pharmacologic target for PPAR␥ agonists (37).…”

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.…”