Abstract
Abstract. The present review explored the anti-inflammatory and immunomodulatory properties of vitamin E, which has protective action against osteoporosis. A systematic review of the literature was conducted to identify the published bone studies on vitamin E. The studies included inflammatory or immunology-related parameters. Medline and Scopus databases were searched for relevant studies published from 2005 till 2015. Research articles published in English and confined to the effect of vitamin E on bone were included. It is pertinent to mention that these studies took into consideration inflammatory or immunology parameters including interleukin (IL)-1, IL-6, receptor activator of nuclear factor kappa-B ligand (RANKL), inducible nitric oxide synthases (iNOS), serum amyloid A (SAA), e-selection and high-sensitivity C-reactive protein (hs-CRP). An extended literature search yielded 127 potentially relevant articles with seven articles meeting the inclusion and exclusion criteria. Another recent article was added with the total number accounting to eight. All these included literature comprised five animal studies, one in-vitro study and two human studies. These studies demonstrated that vitamin E, especially tocotrienol, was able to alleviate IL-1, IL-6, RANKL, iNOS and hs-CRP levels in relation to bone metabolism. In conclusion, vitamin E exerts its anti-osteoporotic actions via its anti-inflammatory and immunomodulatory effects.
References
1 (1991) Free radical recycling and intramembrane mobility in the antioxidant properties of α-tocopherol and α-tocotrienol. Free Radic. Biol. Med. 10, 263–275.
2 (1991) Effect of tocotrienols on hepatocarcinogenesis induced by 2-acetylaminofluorene in rats. Am. J. Clin. Nutr. 53, 1076S–1081S.
3 (2011) Direct inhibition of osteoclast formation and activity by the vitamin e isomer gamma-tocotrienol. Int. J. Vitam. Nutr. Res. 81(6), 358–367.
4 (2004) Tocotrienol-rich fraction from palm oil affects gene expression in tumors resulting from MCF-7 cell inoculation in athymic mice. Lipids. 39, 459–467.
5 (2003) Molecular basis of vitamin E action: tocotrienol modulates 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration. J. Biol. Chem. 278, 43508–43515.
6 (2002) Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction (TRF25) of rice bran in hypercholesterolemic humans. Atherosclerosis. 161, 199–207.
7 (2010) Comparison of the effects of tocopherol and tocotrienol on osteoporosis in animal models. Int. J. Pharm. 6, 561–568.
8 (2011) Tocotrienol as an anti-osteoporotic agent: The progress so far. Int. J. Osteoporosis Metab. Disorders. 4, 1–14.
9 (2012) Vitamin E and bone structural changes: An evidence-based review. E-CAM 2012. 2012. Article ID 250584, 14 pages.
10 (2008) Palm tocotrienol exerted better antioxidant activities in bone than alpha-tocopherol. Basic Clin. Pharmacol. Toxicol. 103, 55–60.
11 (2010) Vitamin E exhibit bone anabolic properties. J. Bone Miner. Metab. 28, 149–156.
12 (2010) Beneficial effects of vitamin E supplementation on the static and dynamic bone histomorphometric parameters in normal male rats. J. Bone Miner. Metab. 28, 503–509.
13 (2010) Effects of α-tocopherol on the early phase of osteoporotic fracture healing. J. Orthop. Res. 29, 1732–1738.
14 (2012) Effects of alpha-tocopherol supplementation on fracture healing in postmenopausal osteoporotic rat model. Clinics (Sao Paulo). 67(9), 1077–1085.
15 (2012) Effects of low-dose versus high-dose γ-tocotrienol on the bone cells exposed to the hydrogen peroxide-induced oxidative stress and apoptosis. Evid. Based Complement. Alternat. Med. 2012, 680834.
16 (2006) Osteoimmunology: interplay between the immune system and bone metabolism. Annu. Rev. Immunol. 24, 33–63.
17 (2004) Hand cortical bone mass and its associations with radiographic joint damage and fractures in 50–70 year old female patients with rheumatoid arthritis: cross sectional Oslo-Truro-Amsterdam (OSTRA) collaborative study. Ann. Rheum. Dis. 63, 1331–1334.
18 (2005) Prevalence of and risk factors for low bone mineral density and vertebral fractures in patients with systemic lupus erythematosus. Arthritis Rheum. 52, 2044–2050.
19 (2005) Prevalence of osteoporosis and osteopenia among African Americans with early rheumatoid arthritis: the impact of ethnic-specific normative data. J. Natl. Med. Assoc. 97, 1155–1160.
20 (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N.Y. Acad. Sci. 908, 244–254.
21 (2000) The prevalence of vertebral fractures in mild ankylosing spondylitis and their relationship to bone mineral density. Rheumatology (Oxford). 39, 85–89.
22 (2000) Bone versus immune system. Nature. 408, 535–536.
23 (2003) Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc. Natl. Acad. Sci. USA. 100, 9090–9095.
24 (2002) IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev. 13, 357–368.
25 (2002) Treatment of interleukin–1 receptor antagonist in combination with methotrexate (MTX) in rheumatoid arthritis patients. Arthritis. Rheum. 46, 614–624.
26 (1992) Modulation of osteoclast differentiation. Endocr. Rev. 13, 66–80.
27 (1989) Generation of osteoclasts from isolated hematopoietic progenitor cells. Blood. 74, 1295–1302.
28 (2000) Interleukin-6: the endocrine cytokine. J. Clin. Endocrinol. Metab. 85(3), 1331–1333.
29 (2001) Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. J. Biol. Chem. 276, 563–568.
30 (2000) TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J. Clin. Invest. 106, 1481–1488.
31 (2002) Systemic TNFα promotes erosive bone resorption by increasing the number of CD11b+ osteoclast progenitors in the periphery which are dependent on RANK signaling for osteoclastogenesis. J. Bone Miner. Res. 17S, 130.
32 (2003) Mechanisms of TNF-α and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J. Clin. Invest. 111, 821–831.
33 (2005) The p55 TNF receptor mediates TNF inhibition of osteoblast differentiation independently of apoptosis. Am. J. Physiol. Endocrinol. Metab. 288, E1011–E1018.
34 (1986) Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature. 319, 516–518.
35 (2006) Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation. Proc. Natl. Acad. Sci. USA. 103, 14925–14930.
36 (2005) Vitamin E: inflammation and atherosclerosis. Annu. Rev. Nutr. 25, 151–174.
37 (2013) Effects of Vitamin E on Bone Biomechanical and Histomorphometric Parameters in Ovariectomized Rats. J Osteoporo. 2013. Article ID 825985, 9 pages.
38 (1999) Dietary effect of tocopherols and tocotrienols on the immune function of spleen and mesenteric lymph node lymphocytes in Brown Norway rats. Biosci. Biotechnol. Biochem. 63, 1697–1702.
39 (1999) Effect of dietary antioxidants on serum lipid contents and immunoglobulinproductivity of lymphocytes in Sprague–Dawley rats. Biosci. Biotechnol. Biochem. 63, 575–576.
40 (2008) Tocotrienol-rich fraction of palm oil exhibits anti-inflammatory property by suppressing the expression of inflammatory mediators in human monocytic cells. Mol. Nutr. Food. Res. 52, 921–929.
41 (2009) Tocotrienols suppressproinflammatory markers and cyclooxygenase-2 expression in RAW264.7 macrophages. Lipids. 44, 787–797.
42 (2010) Dietary supplementation with tocotrienols enhances immune function in C57BL/6 mice. J. Nutr. 140, 1335–1341.
43 (1998) Effects of dietary vitamin E on the immune system in broilers: Altered proportions of CD4 cells in the thymus and spleen. Poult. Sci. 77, 529–537.
44 (2010) Immune response of broiler chickens fed different levels of arginine and vitamin E to a coccidiosis vaccine and Eimeria challenge. Poult. Sci. 89, 1870–1877.
45 (1998) Humoral immune response impairment following excess vitamin E nutrition in the chick and turkey. Poult. Sci. 77, 956–962.
46 (2009) Arginine and vitamin E improve the antibody response to infectious bursal disease virus (IBDV) and sheep red blood cells in broiler chickens. Br. Poult. Sci. 50, 291–297.
47 (2011) Effect of dietary vitamin E on immunological stress of layers and their offspring. J. Anim. Physiol. Anim. Nutr. (Berl). 95, 343–350.
48 (2003) Profile of chicken cytokines induced by lipopolysaccharide is modulated by dietary alpha-tocopheryl acetate. Poult. Sci. 82, 1266–1273.
49 (2009) Effects of different levels of vitamin E on growth performance and immune response of broilers under heat stress. Poult. Sci. 88, 2101–2107.
50 (2005) Tocotrienol offers better protection than tocopherol from free radical-induced damage of rat bone. Clin. Exp. Pharm. Physiol. 32, 761-0.
51 (2013) Tocotrienol supplementation in postmenopausal osteoporosis: evidence from a laboratory study. Clinics (Sao Paulo). 68, 1338–1343.
52 (2007) Effects of vitamin E supplementation on bone metabolism in nicotine-treated rats. Singapore Med. J. 48, 195–199.
53 (2010) Vitamin E reversed nicotine-induced toxic effects on bone biochemical markers in male rats. Arch. Med. Sci. 6, 505–512.
54 (2013) Vitamin E does not prevent bone loss and induced anxiety in rats with ligature-induced periodontitis. Arch. Oral. Biol. 58, 50–58.
55 (2011) α-Tocotrienol inhibits osteoclastic bone resorption by suppressing RANKL expression and signaling and bone resorbing activity. Biochem. Biophys. Res. Commun. 406, 546–551.
56 (2011) Relationship between inflammation biomarkers, antioxidant vitamins, and bone mineral density in patients with metabolic syndrome. Nutr. Res. Pract. 5, 150–156.
57 (2016) Vitamin E homologues α- and γ-tocopherol are not associated with bone turnover markers or bone mineral density in peri-menopausal and post-menopausal women. Osteoporos Int. 27(7), 2281–2290.
58 (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann. Intern. Med. 142(1), 37–46.
59 . (2012) Is Vitamin E bad for your bones? Harv Health. 2012, 37, 4.ff.
60 (2012) Vitamin E decreases bone mass by stimulating osteoclast fusion. Nat. Med. 18(4), 589–594.
61 (2010) Comparison of the Effects of Tocopherol and Tocotrienol on Osteoporosis in Animal Models. Int. J. Pharm. 6(5), 561–568.
62 (1995) Mechanisms of disease: bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N. Engl. J. Med. 332, 305–311.
63 (1998) TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J. Exp. Med. 188, 997–1001.
64 (1995) Cytokines and osteoclast activity. Calcif. Tissue Int. 56, S27–S28.
65 (1998) Cytokines, bone remodeling, and estrogen deficiency: a 1998 update. Bone. 23, 75–81.
66 (1998) Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures. Biochem. Biophys. Res. Commun. 246, 199–204.
67 (2012) The anti-inflammatory role of vitamin e in prevention of osteoporosis. Adv. Pharmacol. Sci. 0, Article ID 142702. doi: 10.1155/2012/142702
68 (2011) Attenuation of oxidative stress, inflammation and early markers of tumor promotion by caffeic acid in Fe-NTA exposed kidneys of Wistar rats. Mol. Cell Biochem. 357, 115–124.
69 (1996) Antioxidant and redox regulation of gene transcription. FASEB J. 10, 709–720.
70 (2007) Osteoporosis and inflammation. Nutr. Rev. 65, S147–S151.
71 (2006) Nicotine induced proliferation and cytokine release in osteoblastic cells. Int. J. Mol. Med. 17, 121–127.
72 (2011) Nicotine exerts an anti-inflammatory effect in a murine model of acute lung injury. Inflammation. 34, 231–237.
73 (2013) Identification and characterization of poly(I:C)-induced molecular responses attenuated by nicotine in mouse macrophages. Mol. Pharmacol. 83, 61–72.
74 (2007) Nicotine protects kidney from renal ischemia/reperfusion injury through the cholinergic anti-inflammatory pathway. PLoS One. 2, e469.
75 (2009) Activation of the cholinergic anti-inflammatory system by nicotine attenuates neuroinflammation via suppression of Th1 and Th17 responses. J. Immunol. 183, 6681–6688.
76 (2009) Nicotinic attenuation of central nervous system inflammation and autoimmunity. J. Immunol. 182, 1730–1739.
77 (2007) Nicotine exposure alters in vivo human responses to endotoxin. Clin. Exp. Immunol. 147, 28–34.
78 (2007) Guidelines on nicotine dose selection for in vivo research. Psychopharmacology (Berl). 190, 269–319.
79 (2004) Oral contraceptives induce CYP2A6 activity and accelerate nicotine metabolism. Clin. Pharmacol. Ther. 75(2), 36.
80 (2005) Exposure to nicotine is probably a major cause of inflammatory diseases among non-smokers. Med. Hypotheses. 65, 253–258.
81 (2012) Effects of dietary vitamin E type and level on lipopolysaccharide-induced cytokine mRNA expression in broiler chicks. Poult. Sci. 91, 1893–1898.
82 (2008) Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases. Proc. Natl. Acad. Sci USA. 105, 20464–20469.
83 (2010) Inhibition of inflammation and carcinogenesis in the lung and colon by tocopherols. Ann. N.Y. Acad. Sci. 1203, 29–34.
84 (1994) Antioxidant properties of alpha-tocopherol and alpha-tocotrienol. Methods Enzymol. 234, 354–366.
85 (1993) Structural and dynamic membrane properties of alpha-tocopherol and alpha-tocotrienol: implication to the molecular mechanism of their antioxidant potency. Biochemistry. 32, 10692–10699.
86 (2005) Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. Semin. Cancer Biol. 15, 277–289.
87 (2000) Inducible nitric oxide synthase and inflammatory diseases. Mol. Med. 6, 347–373.
88 (1998) Inducible nitric oxide synthase in human diseases. Clin. Exp. Immunol. 113, 147–156.
89 (2001) Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-α transgenic mouse model of liver cancer. J. Hepatol. 41, 815–822.
90 (2001) Divergence of the inflammatory response in two types of chickens. Dev. Comp. Immunol. 25, 629–638.
91 (2007) Effect of high-dose α-tocopherol supplementation on biomarkers of oxidative stress and inflammation and carotid atherosclerosis in patients with coronary artery disease. Am. J. Clin. Nutr. 86, 1392–1398.
92 (2014) Cytoprotective effect of tocotrienol-rich fraction and α-tocopherol vitamin e isoforms against glutamate-induced cell death in neuronal cells. Int. J. Vitam. Nutr. Res. 84(3–4), 0140–0151.
93 (2009) Effects of RANKL inhibition on inflammation and immunity. IBMS BoneKEy. 6, 116–126.
94 (2001) TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am. J. Pathol. 159, 1689–1699.
95 (2002) Tumor necrosis factor alpha-mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin. Arthritis Rheum. 46, 785–792.
96 (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 402, 304–309.
97 (2009) Trolox prevents osteoclastogenesis by suppressing RANKL expression and signaling. J Biol Chem. 284(20), 13725–13734.
98 (2004) Higher circulating hs-CRP levels are associated with lower bone mineral density in healthy premenopausal and postmenopausal women: evidence for link between systemic inflammation and osteoporosis. Korean J. Bone Metab. 11, 147–157.
99 (2005) Higher circulating hsCRP levels are associated with lower bone mineral density in healthy pre- and postmenopausal women: evidence for a link between systemic inflammation and osteoporosis. Osteoporos. Int. 16, 1263–1271.
100 (2009) No link between C-Reactive Protein (CRP) and Bone Mineral Density (BMD) in men, but menopause status modifies the relation in women: The Framingham Osteoporosis Study. Arthritis Rheum. 60, 1131.
101 (2007) Bone Mineral Density in adults with the Metabolic Syndrome: analysis in a population based U.S. Sample. J. Clin. Endocrinol. Metab. 92, 4161–4164.
102 (2015) Effect of vitamin E supplementation on serum C-reactive protein level: a meta-analysis of randomized controlled trials. Eur. J. Clin. Nutr. 69, 867–873.
103 (1997) Macrophage prostaglandin production contributes to the age-associated decrease in T cell function which is reversed by the dietary antioxidant vitamin E. Mech. Ageing Dev. 93, 59–77.
104 (1998) Immune function in aged women is improved by ingestion of vitamins C and E. Can. J. Physiol. Pharmacol. 76, 373–380.
105 (2011) Role of immunoregulatory transcription factors in differential immunomodulatory effects of tocotrienols. Free Radic. Biol. Med. 51, 129–143.
106 (2009) Daily supplementation of tocotrienol-rich fraction or alpha-tocopherol did not induce immunomodulatory changes in healthy human volunteers. Br. J. Nutr. 101, 810–815.
107 (2006) Multivitamin/mineral supplements and prevention of chronic disease. Evid. Rep. Technol. Assess. 139, 1–117.
108 (2007) Cross Genome-wide screening of alpha-tocopherol sensitive genes in heart tissue from alpha-tocopherol transfer protein null mice (ATTP−/−). FEBS letters. 581(8), 1572–1578.
109 (1996) Antioxidant and prooxidant activity of alpha-tocopherol in human plasma and low density lipoprotein. J. Lipid Res. 37, 1436–1448.
110 (2016) Association of dietary and serum vitamin E with bone mineral density in middle-aged and elderly Chinese adults: a cross-sectional study. Br. J. Nutr. 115, 113–120.
111 (2003) Gamma-tocopherol, but not alpha-tocopherol, decreases proinflammatory eicosanoids and inflammation damage in rats. FASEB J. 17, 816–822.
112 (2010) Nitric oxide and bone. Ann. NY Acad. Sci. 1192, 391–403.
113 (2015) Circulating concentrations of vitamin E isomers: Association with bone turnover and arterial stiffness in post-menopausal women. Bone. 81, 407–412.
114 (2012) Effects of Vitamin E on Bone Turnover Markers Among US Postmenopausal Women. JBMR. 27(6), 1368–1380.
115 (2014) Effects of vitamin E on bone remodeling in perimenopausal women: Mini review. Maturitas. 79(4), 476–480.