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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-B 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) 2 D 3 . NF-B 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 ϩ 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 ϩ 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-B activation induced by RANKL in vitro. TNF-␣, interleukin (IL)-2, and interferon (IFN)-␥ 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.

Osteoporosis and obesity remain a major public health concern through its associated fragility and fractures. Several animal models for the study of osteoporotic bone loss, such as ovariectomy (OVX) and denervation, require unique surgical skills and expensive set up. The challenging aspect of these age-associated diseases is that no single animal model exactly mimics the progression of these human-specific chronic conditions. Accordingly, to develop a simple and novel model of post menopausal bone loss with obesity, we fed either a high fat diet containing 10% corn oil (CO) or standard rodent lab chow (LC) to 12 month old female C57Bl/6J mice for 6 months. As a result, CO fed mice exhibited increased body weight, total body fat mass (BFM), abdominal fat mass and reduced bone mineral density (BMD) in different skeletal sites measured by Dual Energy X-ray Absorptiometry (DXA). We also observed that decreased bone mineral density (BMD) with age in CO fed obese mice was accompanied by increased bone marrow adiposity, up-regulation of PPARγ, cathepsin k and increased pro-inflammatory cytokines (IL-6 and TNF-α) in bone marrow and splenocytes, when compared to that of LC fed mice. Therefore, this appears to be a simple, novel and convenient age-associated model of post menopausal bone loss, in conjunction with obesity, which can be used in pre-clinical drug discovery to screen new therapeutic drugs or dietary interventions for the treatment of obesity and osteoporosis in the human population.

Gingival inflammation and alveolar bone resorption are hallmarks of adult periodontitis, elicited in response to oral micro-organisms such as Porphyromonas gingivalis. We hypothesized that omega (ω)-3 fatty acids (FA) dietary supplementation would modulate inflammatory reactions leading to periodontal disease in infected rats. Rats were fed fish oil (ω-3 FA) or corn oil (n-6 FA) diets for 22 weeks and were infected with P. gingivalis. Rats on the ω-3 FA diet exhibited elevated serum levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), documenting diet-induced changes. PCR analyses demonstrated that rats were orally colonized by P. gingivalis; increased IgG antibody levels substantiated this infection. P. gingivalis-infected rats treated with ω-3 FA had significantly less alveolar bone resorption. These results demonstrated the effectiveness of an ω-3 FA-supplemented diet in modulating alveolar bone resorption following P. gingivalis infection, and supported that ω-3 FA may be a useful adjunct in the treatment of periodontal disease. Abbreviations: PUFA, polyunsaturated fatty acid; EPA, eicosapentanoic acid; DHA, docosahexanoic acid; and PCR, polymerase chain-reaction.

Fish oil rich in n-3 polyunsaturated fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) protects inflammation induced bone loss in chronic inflammatory diseases like rheumatoid arthritis, periodontitis, and osteoporosis. EPA and DHA differentially regulate functional parameters and gene expression in different cell types. One of the risk factors for bone loss in inflammatory bone diseases is the elevation of bone-resorbing osteoclasts and a very few studies so far have indicated that attenuation of osteoclastogenesis might be one of the mechanisms by which n-3 PUFA exert its effect on bone loss protection. However, the precise mechanism underlying this process remains unclear. Receptor activator of NF-kappaB ligand (RANKL) is known to be the most critical mediator of osteoclastogenesis. Therefore, in this study, we examined the differential effect of EPA and DHA on RANKL-stimulated osteoclastogenesis and RANKL signaling using a murine monocytic cell line RAW 264.7. DHA was found to inhibit osteoclast differentiation, activation and function more potently than EPA. The differential potential also closely correlated with the inhibition of osteoclast-specific genes like tartrate resistant acid phosphatase, cathepsin K, calcitonin receptor, matrix metalloproteinase-9 expression and osteoclast-specific transcription factor, c-Fos, as well as osteotropic proinflammatory cytokine, TNF-alpha to a greater extent with DHA than EPA. Further, pretreatment of RAW 264.7 cells with DHA also showed significantly reduced activation of NF-kappaB and p38MAPK than EPA. Our findings suggest that DHA may be much more effective than EPA in alleviating RANKL induced proinflammatory cytokine production, intracellular signaling activation, thereby decreasing osteoclast activation and bone resorption.

The longevity of mice of the (NZB X NZW)Fj (B/W) strain and the DBA/2f strain of mice is dramatically prolonged by dietary restriction. B/W mice are susceptible to, and die at an early age from, immunocomplex nephritis. Mice Edelman et al. (20) found that in man protein and protein/calorie deprivation leads to deficiencies of cellular immunity attributable to deficiency in function of thymusdependent (T)-lymphocytes.Jose et al. (21) observed that although malnourished Australian aboriginal children frequently exhibited rheumatic heart disease, they rarely showed symptoms attributed in well-nourished populations to post-streptococcal rheumatic fever. Jose et al. (22) showed that antibody responses of these nutritionally deprived aboriginal children to certain antigens can be grossly deficient, whereas in vitro responses of T-lymphocytes to plant lectins are better preserved. Because analysis of the relationship of immunologic perturbations to the nutritional deficiency may be difficult under field conditions, we launched an analysis of the influence of nutrition on immune functions of experimental animals under controlled laboratory conditions. Jose et al. (23-26), Cooper et al. (27), Good et al. (28,29), and Kramer and Good (30) showed that in mice, rats, and guinea pigs moderate chronic dietary protein restriction depresses antibody production while increasing or permitting maintenance of certain cell-mediated immunities. Extreme protein deprivation produced deficiency of both cellular and humoral immunity. Profound nutritional deficiencies exerted influences from which the animals were slow to recover. In an earlier study with NZB mice we observed that breeding capacity is deficient (31). Comparisons were made, using two commercial diets that differed in proportion of animal fat and proAbbreviations: B/W, (NZB X NZW)F1 mice; calorie, the nutritionists' calorie, = 1 kcal, = 4.18 kJ, is used throughout this paper.tein. Reduction of dietary fat decreased reproductive success but prolonged life and decreased propensity to autoimmunity in NZB mice (32,33). A well-defined diet low in protein resulted in maintenance of cell-mediated and humoral immunity functions which usually decline with age in NZB mice (34)(35)(36). Autoimmune hemolytic anemia was slower to develop but was not prevented, nor was longevity increased. These studies dissociated to some degree changes in immunoglobulin levels and the declining vigor of cell-mediated immunity of NZB mice from expression of lethal autoimmune anemia. Dubois et al. (37) also noted that a low-phenylalanine and low-tyrosine diet interfered with disease expression and prolonged the life of (NZB X NZW)F1 mice.The present investigation concerns influence of different diets on longevity of short-lived, autoimmunity-susceptible mice. (NZB X NZW)F1 (B/W) mice were studied because this hybrid is short-lived due to the development of autoimmune renal disease early in life (38,39

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These findings suggest that diets enriched for omega-3 FA modulate the local gingival inflammatory milieu of the host following oral P. gingivalis infection, which impacts on alveolar bone resorption in rats.