Abstract
BackgroundEvidence from epidemiological, clinical and animal studies suggests a link may exist between low bone density and cardiovascular disease, with inflammatory mediators implicated in the pathophysiology of both conditions. This project examined whether supplementation with soy isoflavones (IF), shown to have anti-inflammatory properties, could prevent tissue expression of TNF-α and the development of skeletal pathology in an animal model of chronic inflammation.MethodsEight-week old, intact, female C57BL/6J mice were used. In Phase 1, a lipopolysaccharide (LPS)-dose response study (0, 0.133, 1.33 and 13.3 μg/d) was conducted to determine the LPS dose to use in Phase 2. The results indicated the 1.33 μg LPS/d dose produced the greatest decrease in lymphocytes and increase in neutrophils. Subsequently, in Phase 2, mice were randomly assigned to one of six groups (n = 12–13 per group): 0 or 1.33 μg LPS/d (placebo or LPS) in combination with 0, 126 or 504 mg aglycone equivalents of soy IF/kg diet (Control, Low or High dose IF). Mice were fed IF beginning 2 wks prior to the 30-d LPS study period.ResultsAt the end of the study, no differences were detected in final body weights or uterine weights. In terms of trabecular bone microarchitecture, μCT analyses of the distal femur metaphysis indicated that LPS significantly decreased trabecular bone volume (BV/TV) and number (TbN), and increased separation (TbSp). Trabecular bone strength (i.e. total force) and stiffness were also compromised in response to LPS. The High IF dose provided protection against these detrimental effects on microarchitecture, but not biomechanical properties. No alterations in trabecular thickness (TbTh), or cortical bone parameters were observed in response to the LPS or IF. Immunohistomchemical staining showed that tumor necrosis factor (TNF)-α was up-regulated by LPS in the endothelium of small myocardial arteries and arterioles as well as the tibial metaphysis and down-regulated by IF.ConclusionThese results suggest IF may attenuate the negative effects of chronic inflammation on bone and cardiovascular health. Additional research is warranted to examine the anti-inflammatory properties of the soy isoflavones and the mechanisms underlying their prevention of chronic inflammation-induced bone loss.
Highlights
Evidence from epidemiological, clinical and animal studies suggests a link may exist between low bone density and cardiovascular disease, with inflammatory mediators implicated in the pathophysiology of both conditions
The three relatively low doses of LPS utilized in this study produced no detectable alterations in animal behavior in terms of grooming, food consumption and physical activity, but localized edema did develop around the pellet and was resolved within the first week of the study
The absence of an effect on body weight combined with no noticeable alterations in food intake or grooming behavior, confirms our previous observation [36] in which chronic exposure to LPS at the dose used in the present study induced a low-grade inflammation but did not negatively impact basic animal behaviors
Summary
Evidence from epidemiological, clinical and animal studies suggests a link may exist between low bone density and cardiovascular disease, with inflammatory mediators implicated in the pathophysiology of both conditions. Osteopenia is a common complication with conditions associated with chronic elevation of pro-inflammatory mediators and has been linked to increased incidence of cardiovascular morbidity and mortality [1,2] This association between low bone density and vascular disease is supported by population studies [1,2,3,4] and clinical evidence [2,5,6], including the recent observation that cardiovascular disease risk in postmenopausal women increased relative to the severity of their osteopenia [7]. In a rodent model of chronic inflammation, we have recently demonstrated that a 90 day exposure to LPS results in a decrease in bone density localized to the trabecular bone, pervascular fibrosis and disruption of the intima in intramural arteries This provides further evidence to support a link among the immune, skeletal and cardiovascular systems. The association between reduced bone mass and increased risk of cardiovascular disease may be due in part to the presence of a persistent inflammatory state
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