Metabolic Processes of OA
For many years, osteoarthritis (OA) has primarily been associated with aging (1). Osteoarthritis is usually initiated by damage as a result of injury or continued chronic overuse and mechanical strain on the joints (2). Young adults suffering acute trauma from sports or acute injuries that cause ligament or meniscal tears also have a high incidence of osteoarthritis (3). Muscle weakness also leads to a high incidence of osteoarthritis, suggesting that the muscular structure stabilizes the joint to support proper alignment and lessening of load on articular cartilage (4). Initial damage to a joint leads to generalized pain which restricts range of motion and may or may not be seen by radiographic examination in the early stages of the disease (5). Though injury or overuse may cause initial joint pain, other factors such as genetics, obesity, and diet all contribute to the development of osteoarthritis. New insights, in fact, have shown that after the initial damage, there is an essential change in the joint which causes a chronic increase in arachidonic acid (AA) metabolism that increases inflammation and can also destroy cartilage.
The Western diet has changed dramatically in recent times with increased consumption of omega-6 oils, including AA, and decreased consumption of omega-3 oils. Arachidonic acid is derived from the dietary essential fatty acid (EFA), linoleic acid and a-linolenic acid, respectively, by sequential desaturation and elongation (6), and also by dietary intake. An overabundance of AA in the diet and elevated production in the body has shifted the balance of fatty acid metabolism toward an increase in pro-inflammatory metabolite generation, via the LOX (5-lipoxygenase) and COX (cyclooxygenase) enzymatic pathways (see below). These pro-inflammatory, AA metabolites have been found to play an integral role in the pathophysiology of osteoarthritis (7).
Fatty acid imbalances are commonly seen in patients with chronic inflammatory conditions such as arthritis. Fatty acid levels in bone have been shown to be 50-90% higher in osteoarthritis patients compared to controls (8). In addition, depending on the severity of osteoarthritis, there is an associated accumulation of total fatty acids and EFA in the chondrocytes in osteoarthritis patients suggesting a strong involvement of fatty acid metabolism in the etiology of the disease. Clinical studies have also shown a strong linkage between metabolic defects in EFA metabolism or an overabundance of fatty acids that lead to osteoarthritis through key metabolic mediators (9). These metabolic mediators include cytokines and eicosanoids, whose production is greatly impacted by levels of fatty acids in the body and the underlying metabolic processes making osteoarthritis primarily a metabolic disease (10).
Recent evidence has suggested that certain key nutrients known as flavonoids (found in fruits, vegetables, nuts, grains, tea, and even red wine) are effective at restoring the proper metabolic balance of inflammatory metabolites at the cellular level. They have naturally effective anti-inflammatory and antioxidant properties which, in sufficient quantities, can help in the dietary management of the metabolic aspects of osteoarthritis (11-14). Flavonoids exhibit their beneficial effects on two key metabolic processes affecting osteoarthritis on COX and LOX:
Arachidonic Acid Metabolism on COX & LOX Pathways
Arachidonic acid (AA) is an essential fatty acid, produced naturally by the body and found in the normal diet. Metabolism of AA generates necessary fatty acid molecules for platelet aggregation, maintenance of stomach mucosa, organ function, proper blood flow, urine production, blood pressure, partrition, egg implantation, tissue repair, and viral immunity (15-16). However, when joints are damaged through age, trauma, genetics or general wear and tear, the body releases membrane components called phospholipids into the joint tissue. Phospholipids are then converted to AA (9,17-18). AA is then metabolized via the LOX [5-lipoxygenase (5-LOX)] and the COX [cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)] pathways into leukotrienes, thromboxanes, prostaglandins, and prostacyclins (19). Both LOX and COX pathways have significant impact on the progression of osteoarthritis.
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.
Oxidative Activity
Oxidative activity determines the body’s ability to absorb reactive oxygen species (ROS) (also called oxygen free radicals or oxidative products) that are generated by a variety of endogenous and exogenous processes. Production of ROS generally is the result of tissue damage, or directly causes tissue damage, associated with osteoarthritis (30). While epidemiological studies are complex and probably require further validated method development, experts do agree that ROS play a key role in the degradation of cartilage, a key factor in the etiology of osteoarthritis (31-32). In osteoarthritis patients, F2-isoprostanes, 4-hydroxynonenal, and malondialdehyde, products of ROS AA oxidation which directly degrade cartilage, are elevated in synovial fluid and serum (31). Elderly and aging populations, because of reduced nutritional intake, and lowered ability to ingest, adsorb, and digest foods, generally take in reduced levels of antioxidants (33). Poor intake of antioxidants in conjunction with oxidative stress has been associated with chronic disease states in the elderly (34). Conversely, intake of antioxidants has been shown to improve osteoarthritis symptoms (35). Therefore, poor oxidative status and intake of antioxidants has a direct impact on cartilage health and integrity (36).
Some antioxidants, such as Lipoic acid and Coenzyme Q-10 are endogenously produced. Other antioxidants, such as Vitamins C and E, must be obtained from our diet. Good sources of Vitamin C include citrus fruits and juices, green peppers, spinach, broccoli and strawberries. Good sources of Vitamin E include nuts, whole grains, green vegetables and fish oils. Both Vitamins C and E have been shown to reduce oxidative load which may be beneficial in preventing osteoarthritis (37). Flavonoids are naturally occurring phytochemical antioxidants that “soak up” free radicals and convert them into harmless molecules which cannot destroy tissue (38).
ROS generated by WBC influx into the joint cause increased production of the transcription factor NFκB at the cellular level which induces the production of pro-inflammatory cytokines such as TNFα which in turn induces IL-6 (39). TNFα, along with IL-1β and IL-6, are the initial signals that induce further expression of 5-LOX and COX-2 in osteoarthritis (36).
Limbrel has an antioxidant ORAC (Oxygen Radical Absorbency Capacity) score that is higher than Vitamin C (5517 vs. 5000 μmole TE/g) (40). By reducing these key cytokines on a cellular level, via this antioxidant mechanism, Limbrel manages the production of excess inflammatory metabolites which contribute to osteoarthritis. Therefore, Limbrel’s antioxidant capacity may reduce oxidative stress and minimize further cartilage damage caused over time by ROS produced by the action of WBCs or environmental influences.