Background/Purpose:   Obesity is considered the primary preventable risk factor for OA, increasing the risk of developing OA in weight-bearing joints, especially the knee, as well as in non-weight-bearing joints, such as the hand. Obesity is associated with alterations in systemic inflammation as well as locally within the knee joint compartment. Saturated free fatty acids (FFA) in high fat (HF) diets induce pro-inflammatory cytokine production in a Toll-like receptor 4 (TLR4)-dependent manner. Therefore, we hypothesized that HF diet-induced OA is dependent on TLR4. To test this hypothesis, mice replete or deficient in TLR4, as well as DAP12-deficient mice, that have exuberant TLR4 responses, were treated with control or HF diet to induce obesity and OA.

Methods: 12-14 month old female WT (n=12-22), DAP12 KO (n=15-18) and TLR4 KO (n=10) mice were equally randomized to control (CON) or HF diets (10% or 60% kcal from fat, Research Diets) for 12 weeks. Body composition by DXA (Lunar PIXImus), micro-computed tomography (microCT) of knee joints, and serum cytokine analysis was performed at baseline and 12 weeks. Two blinded graders evaluated OA pathology in the medial and lateral femur and tibia using a Modified Mankin OA scoring system. Synovium- infrapatellar fat pad samples and gonadal fat were collected for inflammatory gene expression and histology.

Results: HF diet induced obesity with increased fat mass in all mice independent of genotype compared to CON diet. HF diet significantly increased maximum OA scores in WT and DAP12 KO, but not TLR4 KO mice. Cartilage damage scores and tidemark duplications were significantly increased in HF diet WT and DAP12 KO but not TLR4 KO mice. Interestingly, chondrocyte hypertrophy was significantly suppressed in DAP12 KO mice independent of diet. Glucose intolerance was induced in HF diet WT and TLR4 KO but not DAP12 KO mice. All HF fed mice had increased serum leptin levels compared to their CON groups. Gonadal fat depots increased, adipocytes were significantly hypertrophied, and crown-like structures increased in WT and DAP12 KO but not TLR4 KO mice. However, HF diet failed to increase serum proinflammatory cytokines in any group. Infrapatellar fat pads (IFP) from HF diet WT mice increased in size while IFP from DAP12 KO mice had increased adipocyte hypertrophy and crown-like structures. Synovial thickening or macrophage infiltration was similar between groups independent of diet. IFP gene expression revealed significant changes between DAP12 KO and WT and surprisingly few changes between WT and TLR4 KO.

Conclusion: This study is the first to use middle-aged mice for a short term feeding to induce HF diet-induced OA progression. DAP12 KO and WT mice developed similar OA while TLR4 mice were protected from HF diet-induced progression of OA. HF-diet DAP12 KO mice developed distinct differences in their OA including significantly reduced hypertrophic chondrocytes and significantly increased IFP adipocyte hypertrophy. Our findings show that TLR4 is required for HF-diet induced progression of OA in middle-aged female mice. TLR4-inhibitors may be attractive targets for disease modifying osteoarthritis drugs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-fat-diet-induced-osteoarthritis-progression-is-dependent-on-toll-like-receptor-4/