Figure 1.

Schematic representation of the in vitro effects of celecoxib (CBX) on cartilage degeneration. Cyclooxygenase (COX)-2 expression in the chondrocyte is induced by inflammatory mediators such as IL-1β and TNF-α (1). Subsequently, the prostanoid receptor EP4 is up-regulated via a COX-2-dependent mechanism (2). Increased COX-2 activity results in large concentrations of prostaglandin E₂ (PGE₂) (3). PGE₂ exerts its effects through the prostanoid receptor EP4 (4), resulting in the increased expression of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin repeats (ADAMTS)-5. Furthermore, PGE₂ augments the release of newly formed proteoglycans from cartilage and reduces the synthesis of proteoglycans (5). IL-1β and TNF-α also activate the transcription factors NF-κB and JNK (6), which stimulate the expression of inducible nitric oxide synthase (iNOS) (7), resulting in the formation of nitric oxide (NO) (8). NO has a potential role in inducing chondrocyte apoptosis, inhibiting proteoglycan synthesis and stimulating MMP activity (9). Together, the effects of NO and PGE₂ result in cartilage degeneration. Celecoxib prevents the negative effects of PGE₂ and NO on cartilage destruction by inhibiting both COX-2 and NF-κB/JNK, thereby potentially slowing cartilage degradation in osteoarthritis.