FIG. 11.

Arachidonic acid is liberated from the cell membrane phospholipids by cytoplasmic phospholipase A2 (PLA2). Free arachidonic acid can be metabolized through cyclooxygenase (COX) and the lipoxygenase (LOX) pathways. In the COX pathway, arachidonic acid is enzymatically converted to biological mediators called prostanoids, including prostaglandins (PGs) by specific prostaglandin synthases through several intermediary steps. COX-1 is the constitutive cyclooxygenase and maintains basal levels of prostaglandins, whereas COX-2 is inducible and produces prostaglandins under inflammatory conditions. In the 5-LOX pathway, arachidonic acid is converted into biologically active metabolites, such as leukotrienes (LTB4), which also trigger inflammatory response. Prostaglandin-mediated activation of p38 leads to the stabilization of COX-2 mRNA, which further enhances the prostaglandin production and inflammation through COX-2 pathway. Activated p38-MAPK phosphorylates and activates Runx-2 transcription factor, which triggers the expression of COL10A1 gene. Leukotrienes (LTB4) derived from 5-LOX pathway also activate p38-MAPK as well as ERK1/2 by phosphorylation. Phospho-ERK1/2 can also lead to the activation of Runx-2. Besides activating Runx-2, phospho-ERK1/2 is also known to inactivate and alleviate the inhibitory action of FOXO3a, thus further increasing the COL10A1 gene expression. Naproxen, by inhibiting both the COX-1 and COX-2, causes diversion of arachidonic acid to 5-LOX-pathway-mediated leukotriene production. These leukotrienes (LTB4) in turn upregulate COL10A1 gene expression.