A parental high-fat diet (HFD) enriched in inflammatory omega-6 polyunsaturated fatty acids (n-6 PUFAs) increases the severity of post-traumatic osteoarthritis (PTOA) in adult offspring, a risk factor which lacks therapeutic interventions. This study investigated whether rebalancing the maternal omega-6 to omega-3 fatty acid (n-6/n-3 FA) ratio during pregnancy and lactation could mitigate PTOA severity in adult offspring. Wildtype (WT) and fat-1 female mice, which endogenously convert n-6 to n-3 PUFAs, were fed either a control or n-6-enriched HFD and mated to control-fed males. WT offspring were evaluated developmentally at embryonic day E17.5 and in adulthood for metabolic and musculoskeletal outcomes 12-weeks following destabilization of the medial meniscus (DMM) surgery. WT fetal offspring from fat-1 dams had increased circulating levels of the anti-inflammatory cytokine IL-4 and decreased levels of the inflammatory cytokine TNFα, indicating a less inflammatory systemic environment than offspring from WT dams. Fetal offspring of fat-1 dams also had increased bone volume and bone mineral density. When raised to adulthood, offspring displayed sexually dimorphic metabolic and musculoskeletal responses. Male offspring: Neither maternal diet nor genotype influenced whole body metabolism or cartilage damage following DMM in male offspring. Maternal HFD increased osteophyte severity and increased subchondral bone remodeling in the lateral tibial plateau. Maternal fat-1 genotype mitigated DMM-induced synovitis, but this change did not protect offspring from displaying pain-related behaviors. Female offspring: Maternal HFD increased body fat, cartilage damage, and synovitis following DMM surgery in offspring of WT dams. Maternal HFD also impaired trabecular bone properties at the tibial metaphysis in offspring of both WT and fat-1 dams. Maternal fat-1 genotype did not protect against structural changes in the knee joints following injury. However, female offspring of fat-1 dams were remarkably protected from displaying pain-related behaviors. Furthermore, decreasing the maternal n-6/n-3 FA ratio decoupled the correlation between synovitis and pain-related behaviors in female offspring from fat-1 dams. These findings suggest decreasing the maternal n-6/n-3 FA ratio mitigates OA-related pain behaviors in female offspring, with evidence of sex-specific differences in cartilage damage and pain.
Oestreich et al. (2026) studied this question.