Rheumatoid Arthritis: Jouzeau JY

Jouzeau JY, Moulin D, Koufany M, Sebillaud S, Bianchi A, Netter P. · UMR CNRS-Nancy Université, France. · J Soc Biol. · Pubmed #19094928 No free full text.

Abstract: Peroxisome proliferators activated receptors (PPAR) are ligand-inducible nuclear transacting factors comprising three subtypes, PPARalpha, PPARbeta/delta and PPARgamma, which play a key role in lipids and glucose homeostasis. All PPAR subtypes have been identified in joint or inflammatory cells and their activation resulted in a transcriptional repression of pro-inflammatory cytokines (IL-1, TNFalpha), early inflammatory genes (NOS(2), COX-2, mPGES-1) or matrix metalloproteases (MMP-1, MMP-13), at least for the gamma subtype. PPAR full agonists were also shown to stimulate IL-1 receptor antagonist (IL-1Ra) production by cytokine-stimulated articular cells in a subtype-dependent manner. These anti-inflammatory and anti-catabolic properties were confirmed in animal models of joint diseases where PPAR agonists reduced synovial inflammation while preventing cartilage destruction or inflammatory bone loss, although many effects required much higher doses than needed to restore insulin sensitivity or to lower circulating lipid levels. However, these promising effects of PPAR full agonists were hampered by their ability to reduce the growth factor-dependent synthesis of extracellular matrix components or to induce chondrocyte apoptosis, by the possible contribution of immunosuppressive properties to their anti-arthritic effects, by the increased adipocyte differentiation secondary to prolonged stimulation of PPARgamma, and by a variable contribution of PPAR subtypes depending on the system. Clinical data are scarce in rheumatoid arthritis (RA) patients whereas thousands of patients worldwilde, treated with PPAR agonists for type 2 diabetes or dyslipidemia, are paradoxically prone to suffer from osteoarthritis (OA). Whereas high dosage of full agonists may expose RA patients to cardiovascular adverse effects, the proof of concept that PPAR agonists have therapeutical relevance to OA may benefit from an epidemiological follow-up of joint lesions in diabetic or hyperlipidemic patients treated for long periods of time with glitazones or fibrates. Additionally, cellular and animal studies are required to assess whether partial agonists of PPAR (SPPARMs) may preserve therapeutical properties with potentially less safety concern.

Blain H, Jouzeau JY, Netter P, Jeandel C. · Service de médecine interne C et gérontologie clinique, centre Antonin-Balmes, CHU, Montpellier, France. · Rev Med Interne. · Pubmed #11109595 No free full text.

Abstract: INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of primary prostanoids by blocking the access of arachidonic acid to the active site of the cyclooxygenases (COXs). Because the prostanoids produced by COX-1 appear to play a physiological role (protection of the gastric mucosa, platelet aggregation, vascular homeostasis, maintenance of renal sodium-water balance) while those produced by COX-2 seem mainly to intervene in the inflammatory response and in certain processes associated with cell proliferation, the hypothesis has been put forward that the NSAIDs that are selective COX-2 inhibitors should theoretically be capable of maintaining NSAID therapeutic properties but also have fewer adverse side effects due to the maintenance of prostaglandin production at normal physiological levels. CURRENT KNOWLEDGE AND KEY POINTS: The hypothesis of COX isoenzyme selectivity has led to a proposed classification for COX inhibitors: 1) COX-1 selective inhibitors (low-dosage aspirin); 2) COX non-selective inhibitors (the majority of classified NSAIDs, which when administered over the long term, e.g., in cases of rheumatoid arthritis, cause duodenal ulcers in 20% of cases and gastric hemorrhage in 1-4% of cases/year); 3) COX-2 preferential inhibitors (meloxicam and nimesulide, which have fewer gastric side effects than standard NSAIDs, but which are not risk-free at high doses); 4) COX-2 selective inhibitors (celecoxib and rofecoxib). Preliminary clinical studies have shown that COX-2 selective inhibitors are as efficient as standard NSAIDs and have fewer adverse digestive side effects, thereby confirming the interest of this proposed classification. In the UK, the aforementioned studies have led to the commercialization of rofecoxib for the treatment of pain and osteoarthritis, while celecoxib has been introduced in medical practice in the USA and other countries for the treatment of rheumatoid arthritis and osteoarthritis. FUTURE PROSPECTS AND PROJECTS: Various epidemiological and laboratory studies have indicated that NSAIDs may be able to reduce the risk of cancer (colorectal cancer in particular) and Alzheimer's disease due to their inhibitory activity on COXs, especially COX-2. The therapeutic contribution of COX-2 specific inhibitors has to be more fully evaluated, particularly as these agents could delay the healing of duodenal ulcers and interfere with several COX-2-induced physiological functions. It is therefore suggested that until further information becomes available, this new class of NSAIDs should be used with caution in certain patient populations.

Kirchmeyer M, Koufany M, Sebillaud S, Netter P, Jouzeau JY, Bianchi A. · Laboratoire de Physiopathologie et Pharmacologie Articulaires, UMR 7561 CNRS-Nancy Université, Vandoeuvre-lès-Nancy, France. · Arthritis Res Ther. · Pubmed #19068145 links to  free full text

Abstract: INTRODUCTION: Interleukin-6 (IL-6) is thought to play a pathogenic role in rheumatoid arthritis and synovium is a major source of IL-6 release. We investigated the ability of retinoids to suppress IL-6 expression in IL-1-stimulated synovial fibroblasts, with special care to the contribution of retinoic acid receptor (RAR) and retinoid X receptor (RXR) subtypes, and the implication of the mitogen-activated protein kinase (MAPK) pathway. METHODS: RAR-alpha, -beta, and -gamma and RXR-alpha, -beta, and -gamma levels were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or Western blot in rat synovial fibroblasts stimulated with 10 ng/mL of IL-1beta. Stimulated levels of IL-6 were assessed by RT-qPCR or immunoassays in the presence or absence of 1 microM all-trans retinoic acid (ATRA) (RAR agonist) or 0.3 microM BMS-649 (RXR agonist). The contribution of RAR subtypes was checked with selective agonists or small interfering RNAs. The effect of ATRA on upstream MAPK (p38 MAPK, c-Jun N-terminal kinase [JNK], and extracellularly regulated kinase 1/2 [ERK1/2]) was assessed by Western blot, and the contribution of the ERK1/2 pathway to the activation of pro-inflammatory transcription factors was studied by TransAm assays. RESULTS: Synovial fibroblasts expressed all RAR and RXR subtypes except RXR-gamma. In IL-1-stimulated cells, ATRA, but not BMS-649, reduced IL-6 expression whereas selective RAR agonists were inactive. The inhibitory effect of ATRA on IL-6 was not affected by the silencing of RAR subtypes. ATRA also reduced the phosphorylation of ERK1/2, but not of p38 MAPK or of JNK. The suppressive effect of ATRA on the activation of activator protein-1 (AP-1) and nuclear factor-IL-6 (NF-IL-6) was reproduced by the MEK1 (mitogen-activated protein extracellularly regulated kinase kinase 1) inhibitor PD-98059, whereas ATRA and PD-98059 had no effect on NF-kappaB activation. CONCLUSIONS: Among RAR and RXR agonists, only ATRA inhibited IL-1-induced IL-6 expression in rat synovial fibroblasts by inhibiting ERK1/2 pathway and subsequent activation of AP-1 and NF-IL-6 independently of RAR.

Pacquelet S, Presle N, Boileau C, Dumond H, Netter P, Martel-Pelletier J, Pelletier JP, Terlain B, Jouzeau JY. · Faculté de Médecine, Vandoeuvre-lès-Nancy, France. · J Rheumatol. · Pubmed #12465160 No free full text.

Abstract: OBJECTIVE: To compare the potency of 2 cytokines, interleukin 17 (IL-17) and IL-1beta, on rat cartilage proteoglycan synthesis with special attention to nitric oxide (NO) and peroxynitrite formation. METHODS: Chondrocytes in alginate beads were stimulated with human recombinant (rh) IL-17 (0.03 to 300.0 ng/ml) and/or rhIL-1beta (0.25 to 25.0 ng/ml) in the presence or not of L-NMMA or CuDips. Alternatively, rats were injected with either IL-17 (10.0 micro g) or IL-1beta (1.0 micro g) into each knee joint. NO concentrations were determined by a spectrofluorimetric assay, proteoglycan synthesis by 35SO4-2 incorporation, peroxynitrite generation by immunostaining for 3-nitrotyrosine, and IL-1beta mRNA expression by reverse transcription-polymerase chain reaction. RESULTS: IL-17 inhibited proteoglycan synthesis and increased NO production, both in vitro and in vivo, without inducing expression of IL-1beta mRNA in cartilage. Additive effects were observed when IL-17 was combined with low concentrations of IL-1. Surprisingly, a similar NO synthesis between IL-1 and IL-17 led to a less suppressive effect of IL-17 on cartilage anabolism than with IL-1. Both in vitro and in vivo, peroxynitrite formation was extensive with IL-1beta, but negligible or nonexistent with IL-17. L-NMMA and CuDips completely corrected the suppressive effect of IL-1beta on proteoglycan synthesis, unlike with IL-17. CONCLUSION: These data showed that NO is weakly involved in the IL-17 mediated inhibition of proteoglycan synthesis in rat. NO overload may not be predictive of any inhibitory effect on cartilage anabolism, but instead superoxide is a key regulator of NO contribution to chondrocyte dysfunction. Since IL-17 is a NO-producing cytokine with additive effects when combined with IL-1, it may play a pivotal role in cartilage destruction during rheumatoid arthritis, for which infiltrating cells produce high levels of superoxide and proinflammatory cytokines.