Metabolic enrichment of omega-3 polyunsaturated fatty acids does not reduce the onset of idiopathic knee osteoarthritis in mice

Abstract

Objective We evaluated the effect of a reduction in the systemic ratio of n-6:n-3 polyunsaturated fatty acids (PUFAs) on changes in inflammation, glucose metabolism, and the idiopathic development of knee osteoarthritis (OA) in mice. We hypothesized that a lower ratio of n-6:n-3 PUFAs would protect against OA markers in cartilage and synovium, but not bone. Design Male and female fat-1 transgenic mice (Fat-1), which convert dietary n-6 to n-3 PUFAs endogenously, and their wild-type (WT) littermates were fed an n-6 PUFA enriched diet for 9-14 months. The effect of gender and genotype on serum PUFAs, IL-6, TNF-α, and glucose tolerance was tested by 2-factor analysis of variance. Cortical and trabecular subchondral bone changes were documented by micro-focal computed tomography, and knee OA was assessed by semi-quantitative histomorphometry grading. Results The n-6:n-3 ratio was reduced 12-fold and 7-fold in male and female Fat-1 mice, respectively, compared to WT littermates. IL-6 and TNF-α levels were reduced modestly in Fat-1 mice. However, these systemic changes did not reduce osteophyte development, synovial hyperplasia, or cartilage degeneration. Also the fat-1 transgene did not alter subchondral cortical or trabecular bone morphology or bone mineral density. Conclusions Reducing the systemic n-6:n-3 ratio does not slow idiopathic changes in cartilage, synovium, or bone associated with early-stage knee OA in mice. The anti-inflammatory and anti-catabolic effects of n-3 PUFAs previously reported for cartilage may be more evident at later stages of disease or in post-traumatic and other inflammatory models of OA.

TLR4 Promotes and DAP12 Limits Obesity‐Induced Osteoarthritis in Aged Female Mice

“…Following μCT scanning, joints were prepared for histological evaluation as previously described. (23) Magnification images (×20) were obtained using a Bioquant imaging system (Version 14.1.6; Bioquant Image Analysis Corp, Nashville, TN, USA), and an Osteoarthritis Research Society International (OARSI) score, as well as a modified Mankin scores were assigned under blinded conditions by two experienced graders throughout the medial and lateral tibia and femur . Knee sections containing the IFP were stained with hematoxylin and eosin; an average adipocyte size was quantified using Bioquant software (Version 17.2; Bioquant Image Analysis Corp).…”

Review: Metabolic Regulation of Inflammation in Osteoarthritis

“…Intriguingly, wound healing in an ear-punch model was also improved by reducing the ratio of n-6:n-3 PUFAs (38). In contrast, the development of early-stage idiopathic knee OA in 1 year-old fat-1-transgenic mice was not reduced compared to control littermates despite lower serum IL-6 and TNF levels (39). These studies suggest that the ratio of n-6:n-3 PUFAs has the greatest impact on OA progression under conditions of more acute activation of cellular and humoral immune responses, such as following tissue damage or joint trauma.…”

Polyunsaturated fatty acids and inflammation

“…Fat-1 mice exposed to a high-fat diet or their offspring did not develop obesity-associated inflammation and are protected from insulin resistance (60,61). While fat-1 mice and their offspring have a better bone growth compared to the wild type (62), they are not protected from knee osteoarthritis (63). They are also protected from colitis development through n-6-derived eicosanoids production (38,64).…”