Dietary n-3 Fatty Acids Decrease Osteoclastogenesis and Loss of Bone Mass in Ovariectomized Mice

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Abstract
The mechanisms of action of dietary fish oil (FO) on osteoporosis are not fully understood. This study showed FO decreased bone loss in ovariectomized mice because of inhibition of osteoclastogenesis. This finding supports a beneficial effect of FO on the attenuation of osteoporosis. Introduction: Consumption of fish or n‐3 fatty acids protects against cardiovascular and autoimmune disorders. Beneficial effects on bone mineral density have also been reported in rats and humans, but the precise mechanisms involved have not been described. Methods: Sham and ovariectomized (OVX) mice were fed diets containing either 5% corn oil (CO) or 5% fish oil (FO). Bone mineral density was analyzed by DXA. The serum lipid profile was analyzed by gas chromatography. Receptor activator of NF‐κB ligand (RANKL) expression and cytokine production in activated T‐cells were analyzed by flow cytometry and ELISA, respectively. Osteoclasts were generated by culturing bone marrow (BM) cells with 1,25(OH)2D3. NF‐κB activation in BM macrophages was measured by an electrophoretic mobility shift assay. Results and Conclusion: Plasma lipid C16:1n6, C20:5n3, and C22:6n3 were significantly increased and C20:4n6 and C18:2n6 decreased in FO‐fed mice. Significantly increased bone mineral density loss (20% in distal left femur and 22.6% in lumbar vertebrae) was observed in OVX mice fed CO, whereas FO‐fed mice showed only 10% and no change, respectively. Bone mineral density loss was correlated with increased RANKL expression in activated CD4+ T‐cells from CO‐fed OVX mice, but there was no change in FO‐fed mice. Selected n‐3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) added in vitro caused a significant decrease in TRACP activity and TRACP+ multinuclear cell formation from BM cells compared with selected n‐6 fatty acids (linoleic acid [LA] and arachidonic acid [AA]). DHA and EPA also inhibited BM macrophage NF‐κB activation induced by RANKL in vitro. TNF‐α, interleukin (IL)‐2, and interferon (IFN)‐γ concentrations from both sham and OVX FO‐fed mice were decreased in the culture medium of splenocytes, and interleukin‐6 was decreased in sham‐operated FO‐fed mice. In conclusion, inhibition of osteoclast generation and activation may be one of the mechanisms by which dietary n‐3 fatty acids reduce bone loss in OVX mice.