Effet de l'activation de PPARy sur l'expression de la mPGES-1 et rôle des polymorphismes de PPARy dans l'arthrose

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal

Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes.

ABSTRACT. Objective. Elevated production of prostaglandin E 2 (PGE 2 ) plays an important role in the pathogenesis of arthritis. Recently, an inducible microsomal prostaglandin E synthase-1 (mPGES-1) was identified. This enzyme is functionally coupled with cyclooxygenase-2 (COX-2) and converts the COX product PGH 2 to PGE 2 . We analyzed expression of mPGES-1 in human normal and osteoarthritic (OA) cartilage and determined the effect of different inflammatory agonists on the expression of mPGES-1 in OA chondrocytes. Biochemical, genetic, and clinical evidence indicates that prostaglandin E 2 (PGE 2 ) plays a critical role in inflammation and in the pathophysiology of articular joint diseases, such as rheumatoid arthritis (RA) and osteoarthritis (OA). For example, arthritic joint tissues produce large quantities of PGE 2 1 . Treatment with neutralizing anti-PGE 2 antibodies prevents acute and chronic inflammation in a rat adjuvant arthritis model 2 . More direct evidence for the role of PGE 2 in arthritis has been provided by gene targeting studies. Genetic disruption of either the PGE 2 receptor EP4 3 or cyclooxygenase-2 (COX-2) 4 , one of the key enzymes in PGE 2 biosynthesis, reduced incidence and severity of collagen-induced arthritis in mice. These animals showed reduced inflammation and less cartilage and bone destruction. The role of PGE 2 in arthritis is also supported by effective suppression of pain and inflammatory responses in arthritis by nonsteroidal antiinflammatory drugs (NSAID) that reduce PGE 2 biosynthesis Chondrocytes are a major source of PGE 2 in the joint; the production of this prostanoid can be induced by proinflammatory cytokines, mitogens, mechanical stress, and traum

Representative immunohistochemical staining section for metalloprotease-13 (MMP-13) and cathepsin K in human osteoarthritis subchondral bone

MMP-13 was detected in the osteoblasts (Ob) as well as in the osteoclasts (Oc). Cathepsin K was detected only in osteoclasts. Original magnification, ×100.<p><b>Copyright information:</b></p><p>Taken from "Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling"</p><p>http://arthritis-research.com/content/10/3/R71</p><p>Arthritis Research & Therapy 2008;10(3):R71-R71.</p><p>Published online 25 Jun 2008</p><p>PMCID:PMC2483463.</p><p></p

Effect of diacerein and rhein on the osteoclastic levels of metalloprotease-13 (MMP-13) and cathepsin K

Determination was performed in the conditioned medium for MMP-13 and on cell lysates for cathepsin K. Raw 264.7 cells were incubated for 5 days with RANKL (100 ng/mL), allowing the cells to differentiate into osteoclasts. After this period, the cells were incubated for 2 days together with RANKL in the presence or absence of interleukin-1-beta (IL-1β) (100 pg/mL) and diacerein or rhein (10 or 20 μg/mL). Data are expressed as fold changes compared with IL-1β-treated control, which was assigned a value of 1. Statistical analysis was performed versus IL-1β-treated control. RANKL, receptor activator of nuclear factor-κB ligand.<p><b>Copyright information:</b></p><p>Taken from "Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling"</p><p>http://arthritis-research.com/content/10/3/R71</p><p>Arthritis Research & Therapy 2008;10(3):R71-R71.</p><p>Published online 25 Jun 2008</p><p>PMCID:PMC2483463.</p><p></p

Effect of diacerein and rhein on metalloprotease-13 (MMP-13) production in human osteoarthritis subchondral bone

Subchondral bone explants were incubated for 5 days with or without interleukin-1-beta (IL-1β) (5 ng/mL) and diacerein or rhein (10 or 20 μg/mL). Data are expressed as fold changes compared with IL-1β-treated control, which was assigned a value of 1. Statistical analysis was performed versus IL-1β-treated control.<p><b>Copyright information:</b></p><p>Taken from "Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling"</p><p>http://arthritis-research.com/content/10/3/R71</p><p>Arthritis Research & Therapy 2008;10(3):R71-R71.</p><p>Published online 25 Jun 2008</p><p>PMCID:PMC2483463.</p><p></p

Effect of diacerein and rhein on subchondral bone osteoblast intracellular mitogen-activated protein (MAP) kinase pathways

Subchondral bone osteoblasts were pre-incubated for 2 hours with diacerein or rhein at 20 μg/mL and incubated for 30 minutes in the presence or absence of interleukin-1-beta (IL-1β) (100 pg/mL). Levels of phosphorylated extracellular signal-regulated kinase-1/2 (ERK1/2), p38, and stress-activated protein kinase/c-jun N-terminal kinase (SAPK/JNK) (p46 and p54) MAP kinases were studied by Western blot and quantified by densitometry as described in Materials and methods. Data are expressed as fold changes compared with IL-1β-treated control, which was assigned a value of 1. Statistical analysis was performed versus IL-1β-treated control.<p><b>Copyright information:</b></p><p>Taken from "Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling"</p><p>http://arthritis-research.com/content/10/3/R71</p><p>Arthritis Research & Therapy 2008;10(3):R71-R71.</p><p>Published online 25 Jun 2008</p><p>PMCID:PMC2483463.</p><p></p