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...

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This paper is available online at http://dmd.aspetjournals.org ABSTRACT:Catechols are a class of substances from natural or synthetic origin that contain a 1,2-dihydroxybenzene group. We have characterized the glucuronidation by rat liver microsomes and by the rat liver recombinant UDP-glucuronosyltransferase isoforms UGT1A6 and UGT2B1 of a series of 42 structurally diverse catechols, including neurotransmitters, polyphenols, drugs, and catechol estrogens. Small catechols (4-nitrocatechol, 2,3-dihydroxybenzaldehyde, 4-methylcatechol, and tetrachlorocatechol), tyrphostine A23, and octylgallate were glucuronidated at the highest rate by rat liver microsomes and the recombinant enzymes. By contrast, polyphenols from green tea (catechin and related compounds), 3,5-dinitrocatechol, the catechol-O-methyltransferase inhibitor drugs (entacapone, nitecapone, and tolcapone), the carboxyl catechols (gallic acid and dihydroxybenzoic acid derivatives), and the neurotransmitters and dopaminergic drugs, except dobutamine, were glucuronidated at low rate. Glucuronidation of most catechols was increased upon treatment of rats by 3-methylcholanthrene (3-MC) or Aroclor 1254. No induction was observed after administration of phenobarbital and clofibrate or treatment with catechols. Partial least-squares modeling was carried out to explain the variations of glucuronidation activity by liver microsomes of nontreated and 3-MC-treated rats. The model developed explained 82% and predicted 61% of the variations of glucuronidation activities. Among the 17 electronic and substructure parameters used that characterize the catechols, the hydrophobicity/ molar volume ratio of catechols showed a strong positive correlation with the glucuronidation rate. The effect of the pK a of the catechol group was modeled to be nonlinear, the optimal pK a value for glucuronidation being between 8 and 9. Hydrogen bonding and steric effects also were important to account for to predict the glucuronidation rates.

The intricate regulation of Spot 14 expression in rat lipogenic tissues has provided a useful tool in studying nutritional and hormonal factors involved in transcription. To gain insight into its function and its possible involvement in human lipid disorders, we cloned human and mouse Spot 14 genes that shared with the rat gene a strong homology concerning the deduced amino acid sequence (81 and 94%, respectively) as well as the promoter region. The mouse promoter was characterized by transfection studies, while quantitative RT-PCR and in situ hybridization experiments showed that Spot 14 is expressed in human liver and, at a high level, in multiple symmetric lipomatosis nodules.

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