While the COX pathway has received much attention, due to the focus on NSAIDs and selective COX-2 inhibitors, there is less awareness of the LOX pathway and its importance in osteoarthritis. LOX pathway and its production of leukotrienes have also been widely studied in asthma, particularly with respect to Singulair®. The LOX pathway in osteoarthritis is responsible for converting AA into chemoattractant, fatty acid molecules called leukotrienes. Leukotriene B4 (LTB4), in particular, causes an influx of fluid and white blood cells (WBC) to the site of damage to aid in tissue repair (10,20).

Metabolically-derived, enzymatic products of AA are required in the body to perform important functions. Yet when these metabolites are chronically present at elevated levels, they can cause severe damage to cartilage. PGE2 causes degradation of cartilage proteoglycan in osteoarthritis and the inhibition of rebuilding of collagen and proteoglycans (21). The continual presence of LTB4 causes the influx of fluid and white blood cells (WBC) into the synovium which initiates new rounds of reactive oxygen species (ROS) production, up-regulation of the inflammatory cascade, continual breakdown of cellular membranes leading to more AA generation and finally, increased expression of both 5-LOX and COX-2 chronically over time (22). Further evidence has shown that when COX pathway inhibitors are added to synovial membrane explants, AA is shunted down the LOX pathway yielding increased concentrations of LTB4 (23). So, it is possible that when patients are on COX pathway inhibitors, either NSAIDs or selective inhibitors, AA metabolism in the LOX pathway continues chronically to produce inflammatory mediators that cause continual destruction of cartilage.

The primary metabolic conversion of AA by COX-1, a constitutively produced enzyme in the body, leads to the generation of prostaglandins and thromboxanes. These physiologically important fatty acid molecules help regulate normal physiological functions, such as platelet aggregation, protection of the stomach lining, and maintenance of normal kidney function (24). When prostaglandins are down-regulated in the stomach, 5-LOX is up-regulated (25). 5-LOX then metabolizes AA to LTB4 acts to attract WBCs to the stomach mucosa causing an inflammatory reaction which results in ulceration (26-27).

A balance of AA metabolites from COX-1 & COX-2 pathways is important for normal physiologic functions. For example, two AA metabolites required for maintenance of normal kidney and cardiovascular functions are thromboxanes and prostacyclins (28). Thromboxanes produced by the metabolic activity of COX-1 in platelets are required for activation of platelets for proper blood clotting also cause vasoconstriction in arteries and arterioles in the cardiovascular system. Prostacyclins, generated from metabolism of AA by COX-2, are required for vasodilation and are antagonistic to thromboxanes (29). If the production of prostacyclins is selectively inhibited, then thromboxanes dominate, constricting arteries and arterioles causing decreases in renal urine perfusion and reduced blood flow in the cardio microvasculature. Decreased urine perfusion leads to increased systolic blood pressure and peripheral edema, while decreased blood flow to the heart can starve the tissue of oxygen and nutrients, especially in the presence of pre-existing atherosclosis (29). Both of these events predispose patients with a history of cardiovascular disease to heart attack and stroke.

Limbrel is unique because its flavonoid ingredients work across both LOX and COX enzymatic pathways. A balance of COX-1 & COX-2 AA metabolism plus a unique Dual Inhibition mechanism of action reduces the possibility of severe side effects while providing effectiveness to the patient in the dietary management of the metabolic aspects of osteoarthritis.

References