Management of Musculoskeletal Manifestations in Inflammatory Bowel Disease

Figure 1

Effects of NSAIDs and selective COX-2 inhibitors. Phospholipase A2 acts on the membrane phospholipids to yield arachidonic acid (AA). AA is metabolized by either cyclooxygenase (COX) or lipoxygenase (LOX) pathway. Two unique COX isoenzymes convert AA into prostaglandin endoperoxides. COX-1 is expressed constitutively in most cells, including GI mucosal cells. In contrast, COX-2 is expressed by inflammatory cells in response to a variety of stimuli including microbial products and cytokines. COX-1 generates prostanoids responsible for “housekeeping” function; they help with vasodilatation, preserving mucosal flow, and induction of platelet aggregation in response to vascular injury to prevent blood loss. COX-2 induction plays a part in leucocyte activation, adherence, and angiogenesis through effects on NFκB and IL8. Reactive oxygen species generated due to enzymatic activities of COX and LOX also stimulate NFκB and perpetuate the cycle. Inhibition of COX-2 prevents this inflammatory cascade and is responsible for clinical effects of NSAIDs and selective COX-2 inhibitors. NSAIDs, in addition, also block COX-1 pathway leading to mucosal injury, vasoconstriction, mucosal ischemia, and increased vascular permeability. NSAIDs may also lead to direct epithelial damage and mitochondrial uncoupling of oxidative phosphorylation. Dashed red line indicates enzymatic inhibition.