Overview

Osteoarthritis (OA), or degenerative joint disease, is the most prevalent joint disorder in dogs, affecting up to 20% of the adult dog population.¹ Mild OA may result in subtle gait changes or intermittent lameness. As the disease progresses, the dog may become less active, show visible lameness, have difficulty rising or laying down, express pain, or have difficulty posturing to urinate or defecate.

OA is associated with inflammation and increased degradation or loss of proteoglycans from the extracellular matrix, resulting in a morphologic breakdown in articular cartilage.²

There is no known cure for OA, so treatment is focused on controlling pain, improving joint function and slowing the degenerative process within the joint.³ Standard medical careusually involves weight management, controlled exercise, and anti-inflammatory and analgesic medications. In addition to medical therapy, dietary management can play an important role in the clinical management of dogs with OA.

Molecular view of OA

Selection and implementation of appropriate therapies for a patient with OA are dependent not only on an understanding of the clinical and gross pathologic changes associated with OA, but also an understanding of the cellular and metabolic pathways involved. In recent years, advances in canine genetics and genomics have lead to powerful tools by which nutrition researchers can examine cellular response to OA. Using these tools, a comprehensive view of the cells response to OA can be determined. Several key experiments now reveal a better understanding of the biology of OA, and help in understanding the best nutritional management of the arthritic dog.

While osteoarthritis (OA) is perceived as a structural disease, the underlying pathology and chronic changes occur at a cellular and molecular level. The imbalance between anabolic and catabolic factors leading to degradation of articular cartilage in OA involves many factors at the molecular level. Gene expression analysis reveals changes in the expression of various structural proteins of the extracellular matrix, inflammatory cytokines, catabolic and anabolic enzymes and cell signaling molecules.⁴

Coupled with numerous OA gene-expression studies, it is clear that inflammatory pathways play a critical role in the chondrocytes response to injury and subsequent progression toward repair or toward arthritis. When compared to normal cartilage, OA-affected cartilage behaves somewhat like an activated macrophage, with up-regulation in expression of interleukin (IL)-1, IL-6 and IL-8 genes. Further examination of either mRNA or specific protein levels (via ELISA) demonstrated arthritis-associated elevations in prostaglandin (PG)E2, tumor necrosis factor (TNF)-α, nitric oxide, and matrix metalloproteinase (MMP)-1, -2, -3, -9, -10 and -13.^5-7 These data suggest a direct connection between the elevation of these inflammatory markers and the structural changes seen in the arthritic joints.

A primary target of medical treatment in OA is inhibition of the cyclooxygenase (COX) enzymes, especially the COX-2 enzyme, via use of non-steroidal anti-inflammatory drugs (NSAIDs).^8-10 The use of COX-2 selective inhibitors can decrease prostaglandin E₂ (PGE2) concentrations and block inflammatory pathways involved in OA, as well as reduce pain and lameness.^{8, 9, 11-14}

Nutritional opportunities in OA

Another means of reducing PGE2 and production of inflammatory mediators is through the use of dietary long chain omega-3 (n-3) polyunsaturated fatty acids (PUFA), especially eicosapentaenoic acid (EPA; 20:5n-3). The primary omega-6 fatty acid in cell membranes is arachidonic acid (AA; 20:4n-6), which serves as the precursor for the production of PGE2, thromboxane A2 and LTB4, potent inflammatory mediators in OA. If the diet is enriched with long chain n-3 PUFA, specifically EPA and docosahexaenoic acid (DHA;22:6n-3), part of the AA in cell membranes will be replaced by these n-3 fatty acids.^15-17 EPA then may be used instead of AA for the production of eicosanoids, resulting in a different and less inflammatory set of compounds (e. g. PGE₃, TXA₃ and LTB₅ instead of PGE₂, TXA₂ and LTB₄).^{15, 16}

Dietary n-3 PUFA also suppress the pro-inflammatory mediators IL-1, IL-2 and TNF in cartilage tissue.^{18, 19} Thus, the substitution of omega-3 for part of the omega-6 fatty acids should result in a reduction in inflammation that would be beneficial in inflammatory conditions, including OA.

A review of studies in arthritic humans indicated that most showed positive results from long-chain n-3 PUFA supplementation.²⁰ Recent research in dogs supports many of these prior studies in humans confirming clinical benefits of dietary n-3 fatty acids in OA. Twenty-two dogs with OA of the hip were given a fatty acid supplement marketed for dogs with inflammatory skin conditions (DVM Derm Caps, DVM Pharmaceuticals, Miami, FL).²¹ When dosed according to the manufacturer's recommended dosage, 13 of 22 dogs had noticeable improvement in their arthritic symptoms within two weeks.²¹ Another, uncontrolled study evaluated dogs with naturally occurring OA of the elbow, using force-plate analysis, before and after being fed a diet enriched with n-3 PUFA. Improvements in vertical peak force were observed within 7 to 10 days on the diet. (Budsberg SC 2004, unpublished)

In yet another study, dogs fed a diet enriched with n-3 PUFA following corrective surgery for ruptured cruciate ligaments showed a significant decrease in synovial fluid PGE2.²² Synovial fluid MMP-2 and MMP-9, enzymes which degrade structural proteins in cartilage, also were decreased in these dogs compared to dogs fed the control diet.

Summary

Osteoarthritis is a disease characterized by an imbalance in catabolic and anabolic factors affecting the degradation and synthesis of the extracellular matrix. New techniques are allowing researchers to characterize this disease and evaluate potential therapeutic and nutritional agents at the cellular and molecular level. Proinflammatory mediators and inflammatory cytokines play a central role in the gene-expression changes, and resulting biochemical changes seen in the arthritic articular chondrocyte. Oral administration of EPA has been shown effective in the nutritional management of osteoarthritis in several species.

References

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6.  Amin AR, Attur MG, Abramson SB (1999) Regulation of nitric oxide and inflammatory mediators in human osteoarthritis-affected cartilage: implication for pharmacological intervention. In: Rubanyi GM, (ed) The Pathophysiology & Clinical Applications of Nitric Oxide. Richmond: Harwood Academic Publishers 1999. pp 397-412.

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17. Waldron MK, Hannah SS, Bigley KE, et al. Neutrophil leukotriene synthesis and superoxide production are differentially modulated by type and amount of dietary n-3 polyunsaturated fatty acids. AOCS 2000; :S118(Abstr).

18. Curtis CL, Rees SG, Little CG, et al. Pathologic indicators of degradation and inflammation in human osteoarthritic cartilage are abrogated by exposure to n-3 fatty acids. Arthritis Rheum 2002;46:1544-1553.

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20. Richardson DC, Schoenherr WD, Zicker SC. Nutritional management of osteoarthritis. Vet Clin N Am Small Anim Pract 1997;27:883-911.

21. Miller WH, Scott DW, Wellington JR. Treatment of dogs with hip arthritis with a fatty acid supplement. Canine Pract 1992;17:6-8.

22. Hansen RA, Waldron MK, Allen KGD, et al. Long chain n-3 PUFA improve biochemical parameters associated with canine osteoarthritis. Proc Am Oil Chem Soc meeting, Cincinnati, May 9-12, 2004.