Osteoarthritis (OA) Pathogenesis

The healthy joint is a highly metabolic organ comprised of cartilage, bone, synovium, neural and supportive muscle tissues whose function is critical to mobility and life quality. In OA joints, the metabolic balance shifts toward catabolism driven by cytokine cascades and inflammatory mediators. Proinflammatory cytokines such as interleukin-1b (IL-1b) and tumor necrosis factor-α (TNF-α), produced by chondrocytes and synoviocytes, decrease anabolic activities such as collagen and proteoglycan synthesis and upregulate the production of catabolic enzymes including matrix metalloproteinases (MMP's). These cytokines and other cytokines (IL-8, IL-6, etc.) also upregulate the expression of proinflammatory enzymes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) that lead to increased production of prostaglandin E2 (PGE2) and nitric oxide (NO). Biomechanical alterations resulting from such factors as joint instability, joint malalignment and obesity perpetuate OA and its degradative biochemical pathways. Increasingly, chondrocyte apoptosis and premature senescence are linked to NO and other oxidative injury. It is clear that OA has characteristics of progressive, premature aging of the joint that are mechanically driven and chemically mediated. Inflammatory changes within the synovium are also characteristic of the disease process. Synovitis is typically located adjacent to diseased or damaged cartilage and bone. Regional cartilage destruction may be exacerbated by the release of proteinases and cytokines from the activated synovium.

Combined, the destructive enzymes and cytokines originating from chondrocytes and synoviocytes breakdown the extracellular matrix of cartilage that is responsible for its mechanical resilience and toughness. Cartilage breakdown products provoke the release of collagenase and other destructive enzymes from activated synoviocytes. Vascular hyperplasia of the synovial membrane, stimulated by pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) secreted from macrophages, fibroblasts and endothelial cells, potentiate the inflammatory process. Increased vascular permeability perpetuates the inflammatory process.

Inflammatory mediators act upon nociceptors to reduce the pain threshold such that simple activities that were formerly comfortable, now result in pain, stiffness and avoidance behaviors. The patient loses muscle strength and cardiovascular fitness while gaining weight. This process affects the family interactions with the pet.

It is logical that therapy should be directed at promoting anabolic functions while mitigating the catabolic processes.

Where's the Evidence for Nutraceuticals?

Nutraceuticals include glucosamine, chondroitin sulfate, and avocado-soybean unsaponifiables. Though omega-3 fatty acids are actually a normal dietary ingredient, I will include them here because they are used therapeutically.

Avocado Soybean Unsaponifiables (ASU)

The benchtop and clinical evidence for efficacy of ASU is consistent and compelling. Prospective, randomized, double-blinded, placebo-controlled parallel-group studies have shown that ASU significantly reduced pain, functional impairment and NSAID reliance in humans suffering from OA in the knees and hips.^1,2 Activated chondrocytes incubated with ASU showed reduced TNF-α, IL-1b, COX-2 and iNOS expression to levels similar to that of normal non-activated chondrocytes.³ The suppression of COX-2 and iNOS expression was paralleled by a significant reduction in PGE2 and nitrite. ASU also reduced TNF-α and IL-1b expression in activated monocyte/macrophage-like cells. These findings demonstrate the antiinflammatory activity of ASU on both chondrocytes and synovial membrane macrophage prototypic cells and provide a scientific explanation for the pain-reducing and antiinflammatory effects of ASU observed in OA patients.³ In a canine study, healthy young adult dogs were divided into 3 groups: (1) Control, (2) 300 mg ASU orally every 3 days, and (3) 300 mg ASU orally once daily.⁴ Knee joint fluid was analyzed prior to supplementation and then each month to measure the levels of two isoforms of transforming growth factor b (TGF-b1 and TGF-b2). ASU, in both dosages, caused an increase in both TGF-b isoforms as compared to the control group. This study provides in vivo evidence for pro-anabolic effects of ASU since TGF-b is a stimulator of extracellular matrix production (type II collagen, proteoglycan) in chondrocytes.⁴ Further evidence of canine in vivo efficacy of ASU was provided in an ACL transection study in which the ASU supplemented group showed reduced development of early OA cartilage and subchondral bone lesions (macroscopic and microscopic lesion severity, subchondral bone loss) as compared to placebo treated controls.⁵ The therapeutic effect appeared to be mediated through inhibition of iNOS and MMP-13. A systematic review of human clinical trials was conducted.⁶ Out of 2,026 studies, 53 randomized human clinical trials (RCTs) met the inclusion criteria. Evidence of efficacy for OA treatment was classified for each nutritional compound (glucosamine and chondroitin sulfate were excluded) as good, moderate or limited. Good evidence was found for ASU, moderate evidence for methylsulfonylmethane (MSM) and SKI306X (a plant extract mixture), and limited evidence for Duhuo Jisheng Wan, cetyl myristoleate, lipids from green-lipped muscles and Harpagophytum procumbens extracts.⁶

ASU, Chondroitin Sulfate (CS), Glucosamine (Glu) Combinations

While the effects of ASU alone are of interest, standard clinical practice typically employs the use of combinations of nutraceutical ingredients. It is possible that ingredient combinations could counteract one another, have no appreciable effect (i.e., wasted ingredients) or have additive or even synergistic actions. A recent study evaluated the effect ASU, CS and ASU + CS combination upon proinflammatory cytokine (IL-1b, TNF-α) expression and PGE2 production from synovial lining surrogate cells.⁷ The ASU + CS combination inhibited IL-1b and TNF-α expression and PGE2 production better than either agent alone.⁷ Another study showed that canine chondrocytes propagated in microcarrier spinner culture retained their cartilage phenotype as evidenced by type II collagen production.⁸ When activated by IL-1b, these cells showed ~ 70% increased PGE2 production. Pre-incubation with ASU + CS + Glu combination decreased PGE2 production ~ 60% below that of non-activated control cells. This study provides evidence of a potent antiinflammatory effect.⁸ A similar effect was noted in activated feline chondrocytes when ASU + CS + Glu pretreated cells were compared to positive (untreated activated cells) and negative (non-activated cells) controls.⁹ Recently, a study was conducted to evaluate the antiinflammatory effect of ASU + epigallocatechin gallate (EGCG) on activated equine chondrocyte cell culture.¹⁰ EGCG is a major antioxidant component of green tea. Chondrocyte activation caused upregulated gene expression of COX-2 and increased PGE2 production and NF-kB nuclear translocation. Individually, ASU and EGCG marginally inhibited COX-2 expression and PGE2 production in activated chondrocytes. In contrast, ASU+EGCG combination reduced COX-2 expression close to that of non-activated control levels, significantly inhibited PGE2 production and NF-kB translocation. NF-kB is an essential transcription factor for COX-2 induction. Inhibition of the NF-kB pathway is known to attenuate COX-2 expression. This study demonstrates that the antiinflammatory activity of ASU and EGCG is potentiated when used in combination.¹⁰ Collectively, a large body of in vitro evidence supports the conclusion that ASU + CS + Glu inhibits the expression and production of proinflammatory mediators in multiple species (canine, feline, equine and human) and in multiple joint cell lines (chondrocytes and synovial lining cells). Millis et al. evaluated 8 hound dogs with chronic induced stifle OA. A recent study arm on this dog colony evaluated DasuquinÒ (Nutramax Labs), a nutraceutical containing Glu + CS + ASU + EGCG. Dogs treated with DasuquinÒ showed increased peak vertical force similar to that seen with various NSAIDs in a previous study arm.¹¹ Though the small study population does not permit meaningful statistical analysis, these data suggest the need for larger scale and longer term in vivo evaluation of DasuquinÒ in the restoration of function and pain relief of dogs with chronic OA.

Omega-3 Fatty Acids

Clinical trials that suggest a therapeutic effect of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), upon OA are frequently reported. One such study of dietary supplementation with fish oil omega-3 fatty acids in osteoarthritic dogs showed a significant improvement in weight-bearing (peak vertical force - PVF) as compared to the control-group diet.¹² The magnitude of improved weight-bearing (+ 5.6%) was of similar magnitude reported in many NSAID trials. Improved PVF was noted in 82% of osteoarthritic dogs fed the omega-3 supplemented diet as compared to 38% fed the control diet.¹² A similar study design was used to compare the effects of a test food supplemented with fish oil omega-3 fatty acids and a control diet on serum fatty acid concentrations and owner- and veterinary-assessed severity of OA.¹³ They reported that the test diet raised blood concentrations of omega-3 fatty acids and improved the owner-assessed ability for the ability to rise from a resting position, play, and walk compared with control dogs (whom showed no improvement).¹³ Another study showed that a diet supplemented with omega-3 fatty acid allowed for more rapid reduction in carprofen dosage in osteoarthritic dogs as compared to dogs fed a diet with a low omega-3 fatty acid content.¹⁴

Conclusion

There is compelling evidence supporting the role of nutraceuticals in joint health. The final question is "how confident are you that your recommended product contains what the label says that it does?" A study of randomly selected nutraceuticals showed that 84% of the products tested did not meet their label claims. Contamination with unwanted ingredients is also a problem within this relatively unregulated industry. Consumer Labs (www.consumerlab.com) reports independent laboratory testing of various products' contents and purity.

References

References are available upon request.