A potential role of 15-deoxy-Δ12,14-prostaglandin J2 for induction of human articular chondrocyte apoptosis in arthritis

Abstract

The cyclopentenone prostaglandin (PG) J2 is formed within the cyclopentenone ring of the endogenous prostaglandin PG D2 by a nonenzymatic reaction. The PG J family is involved in mediating various biological effects including the regulation of cell cycle progression and inflammatory responses. Here we demonstrate the potential role of 15-deoxy-Δ12,14- prostaglandin J2 (15d-PG J2) in human articular chondrocyte apoptosis. 15d-PG J2 was released by human articular chondrocytes and found in joint synovial fluids taken from osteoarthritis or rheumatoid arthritis patients. Proinflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) up-regulated chondrocyte release of 15d-PG J2. PG D2 synthase mRNA expression was upregulated by IL-1β, TNF-α, or nitric oxide. 15d-PG J2 induced apoptosis of chondrocytes from osteoarthritis or rheumatoid arthritis patients as well as control non-arthritic subjects in a time- and dose-dependent manner and in a peroxisome proliferator-activated receptor γ-dependent manner. Peroxisome proliferator-activated receptor γ expression was up-regulated by IL-1β and TNF-α. Inhibition of NF-κB, and the activation of p38 MAPK were also found to be involved in 15d-PG J2-induced chondrocyte apoptosis. Such signal pathways led to the activation of the downstream pro-apoptotic molecule p53 and caspase cascades. Together, these results suggest that 15d-PGJ2 may play an important role in the pathogenesis of arthritic joint destruction via a regulation of chondrocyte apoptosis.