Expression and Regulation of Microsomal Prostaglandin E Synthase-1 in Human Osteoarthritic Cartilage and Chondrocytes

XINFANG LI, HASSAN AFIF, SARANETTE CHENG, JOHANNE MARTEL-PELLETIER, JEAN-PIERRE PELLETIER, PIERRE RANGER, and HASSAN FAHMI

ABSTRACT.

Objective. Elevated production of prostaglandin E₂ (PGE₂) 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 PGH₂ to PGE₂. 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.

Methods. Expression of mPGES-1 mRNA and protein in cartilage was determined by quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. OA chondrocytes were treated with different inflammatory agents, and mPGES-1 protein expression was evaluated by Western blot. Activation of the mPGES-1 promoter was assessed in transient transfection experiments.

Results. Levels of mPGES-1 mRNA and protein were markedly elevated in OA versus normal cartilage. Treatment of chondrocytes with interleukin 1ß (IL-1ß) induced expression of mPGES-1 protein in a dose- and time-dependent manner. This appears to occur at the transcriptional level, as IL-1ß induced expression of mPGES-1 mRNA and the activity of this gene promoter. Tumor necrosis factor-a (TNF-a) and IL-17 also upregulated expression of mPGES-1 protein and displayed a synergistic effect with IL-1ß. Peroxisome proliferator-activated receptor-g ligands, 15-deoxy-Δ^12,14-prostaglandin J₂ and troglitazone, inhibited IL-1ß-induced mPGES-1 protein expression, an effect that was reversed by exogenous PGE₂.

Conclusion. Our study shows that mPGES-1 expression is upregulated in OA versus normal cartilage and that proinflammatory cytokines increased mPGES-1 expression in chondrocytes. These data suggest that mPGES-1 may prove to be an interesting therapeutic target for controlling PGE₂ synthesis. (J Rheumatol 2005;32:887-95)

Key Indexing Terms:

MICROSOMAL PROSTAGLANDIN E SYNTHASE-1
CARTILAGE
CHONDROCYTES
OSTEOARTHRITIS

---

From the Osteoarthritis Research Unit, Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Montréal, Québec, Canada.

Supported by the Canadian Institutes of Health Research (CIHR), Grant IMH-63168, and the Fonds de Recherche en santé du Québec (FRSQ) Subvention d'Établissement de Jeune Chercheur JC2836. S. Cheng is supported by a fellowship from the CIHR Training on Mobility and Posture Deficiencies (MENTOR). H. Fahmi is a Research Scholar of FRSQ.

X. Li, MSc; H. Afif, PhD; S. Cheng, MSc; J. Martel-Pelletier, PhD; J-P Pelletier, MD; H. Fahmi, PhD, Osteoarthritis Research Unit, Centre hospitalier de l'Université de Montréal; P. Ranger, MD, Hopital Sacré-Coeur.

Address reprint requests to H. Fahmi, Osteoarthritis Research Unit, Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame, 1560 rue Sherbrooke est, Montréal, Québec H2L 4M1, Canada. E-mail: h.fahmi@umontreal.ca

Accepted for publication December 29, 2004.

---