Palmitic Acid Enhances RANKL-Induced Osteoclastogenesis, While α-Linolenic and Linoleic Acids Serve as Inhibitory Agents

Background/Objectives: Obesity is associated with increased bone marrow fat content and saturation, which contribute to enhanced osteoclastogenesis and bone loss. Although saturated, monounsaturated, and polyunsaturated fatty acids (FAs) have been reported to differentially affect bone metabolism, their comparative effects and the underlying mechanisms remain unclear. This study compared the effects of palmitic acid (PA), oleic acid (OA), α-linolenic acid (ALA), and linoleic acid (LA) on osteoclastogenesis in vitro and examined the effects of PA-, OA-, and LA-enriched diets on bone metabolism. Methods: Receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL)-stimulated RAW264.7 macrophages were treated with PA, OA, ALA, or LA. The number of osteoclasts, tartrate-resistant acid phosphatase (TRAP) activity, osteoclastic gene and protein expression, NF-κB signaling, reactive oxygen species (ROS)-related fluorescence, and antioxidant-related gene expression were evaluated. The involvement of toll-like receptor 4 (TLR4) signaling was examined using TAK-242. Male C57BL/6J mice were fed high-fat high-sucrose diets enriched with PA, OA, or LA for 8 weeks, and bone mineral density (BMD), plasma bone turnover markers, and osteoclast-related gene expression were assessed. Results: PA enhanced RANKL-induced osteoclastogenesis and NF-κB transcriptional activity, which were partially attenuated by TAK-242. ALA and LA attenuated PA-enhanced osteoclastogenesis and oxidative stress-related responses. Mice fed a PA-enriched diet exhibited lower BMD and higher plasma free fatty acid levels and bone turnover markers. Conclusions: PA promotes RANKL-induced osteoclastogenesis, which can be alleviated by ALA and LA in vitro. These findings suggest that different FAs exert distinct effects on osteoclastogenesis and that dietary FA composition may influence bone metabolism.