Research Article: The Anti-Inflammatory Role of Vitamin E in Prevention of Osteoporosis

Date Published: November 17, 2012

Publisher: Hindawi Publishing Corporation

Author(s): A. S. Nazrun, M. Norazlina, M. Norliza, S. Ima Nirwana.

http://doi.org/10.1155/2012/142702

Abstract

There is growing evidence that inflammation may be one of the causal factors of osteoporosis. Several cytokines such as IL-1, IL-6, RANKL, OPG, and M-CSF were implicated in the pathogenesis of osteoporosis. These cytokines are important determinants of osteoclast differentiation and its bone resorptive activity. Anticytokine therapy using cytokine antagonists such as IL-receptor antagonist and TNF-binding protein was able to suppress the activity of the respective cytokines and prevent bone loss. Several animal studies have shown that vitamin E in the forms of palm-derived tocotrienol and α-tocopherol may prevent osteoporosis in rat models by suppressing IL-1 and IL-6. Free radicals are known to activate transcription factor NFκB which leads to the production of bone resorbing cytokines. Vitamin E, a potent antioxidant, may be able to neutralise free radicals before they could activate NFκB, therefore suppressing cytokine production and osteoporosis. Vitamin E has also been shown to inhibit COX-2, the enzyme involved in inflammatory reactions. Of the two types of vitamin E studied, tocotrienol seemed to be better than tocopherol in terms of its ability to suppress bone-resorbing cytokines.

Partial Text

Osteoporosis is a bone disease, characterized by low bone mass and increased risk of fractures [1]. It is well accepted that osteoporosis can be caused by various endocrine, metabolic, and mechanical factors. However, recently, there are opinions that there may be an inflammatory component in the etiology of osteoporosis [2, 3]. There is plenty of evidence linking inflammation to osteoporosis. Epidemiological studies have identified higher incidence of osteoporosis in various inflammatory conditions such as ankylosing spondylitis, rheumatoid arthritis, and systemic lupus erythematosus [4–7]. This association was also observed clinically whereby the degree of osteoporosis was equivalent to the extent of inflammation. If the inflammation was systemic, bone loss will occur at all skeletal sites, whereas if the inflammation was only restricted to a site, bone loss will only occur locally at that site of inflammation [3]. Elderly patients are more prone to osteoporosis, and this was believed to be connected to the elevated production of proinflammatory cytokines with aging [8, 9].

IL-1 plays an important role in various reactions towards infection, inflammation, and immune activation. This cytokine is produced by various cells but the main producer is the monocyte. In the physiological condition, monocytes do not secrete IL-1 but, under pathological conditions such as septic shock, IL-1 is rapidly released and acts directly on the blood vessels. Other cytokines such as TNF-α and interferon, bacterial endotoxin, virus, and antigen can also stimulate the release of IL-1. Reactive oxygen species such as superoxide radicals have been shown to induce IL-1 production [32, 44]. IL-1 is involved in the pathogenesis of various diseases associated with bone loss such as osteoporosis [45, 46], cancer-induced osteolysis [47], rheumatoid arthritis [48], and osteolysis of orthopedic implants [49]. IL-1 is also an important factor in both in vivo and in vitro bone resorption [50, 51]. It stimulates the formation and activity of osteoclasts, leading to excessive bone resorption. Suda et al. [52] demonstrated that the presence of osteoblast and stromal cells was crucial in the formation of osteoclasts by IL-1. Thomson et al. [53] also reported that osteoblasts secrete a factor that stimulates the bone-resorbing activities of rat osteoclasts. However, Xu et al. [54] demonstrated that rat osteoclasts expressed mRNA to IL-1 receptors, while Yu and Ferrier [55] found that osteoclast is one of the target cells for IL-1. These studies proved that IL-1 can act directly on osteoclasts without the presence of osteoblasts or stromal cells. IL-1 may also promote formation of osteoclasts [56]. It acts by activating nuclear factor κB (NFκB) in osteoclast and prevents its apoptosis [57]. It was found that the estrogen-deficient state in postmenopausal women or ovariectomised rats resulted in increased production of IL-1 by monocyte and other bone marrow cells [58, 59]. Estrogen replacement or IL-receptor antagonist was able to prevent the elevation of IL-1 in ovariectomised rats [60, 61]. Vitamin E was also found to have the ability to suppress IL-1 production by activated monocytes [62]. In a different study, combination of superoxide dismutase and vitamin E was effective in inhibiting IL-1 production by human monocytes [32]. The ability of vitamin E to inhibit IL-1 in the bone environment may have prevented bone loss.

IL-6 is another cytokine that is associated with various pathophysiological processes in humans. It is produced by the haematopoetic and nonhaematopoetic cells when they were exposed to various types of stimulation. During bone remodeling, IL-6 is produced in nanomolar concentrations by stromal cells and osteoblasts under the influence of parathyroid hormone, vitamin D3, growth factor, and other cytokines [63]. IL-6 was also reported to be produced by osteoblasts when stimulated by IL-1, TNF-α, and lipopolysaccharide [64]. McSheeny and Chambers [65] reported that osteoblasts were stimulated by local IL-1 to produce IL-6, which was responsible for the activation of osteoclasts. IL-6 promoted the differentiation of osteoclasts from its precursor and played an important role in the pathogenesis of osteoporosis due to estrogen deficiency [66, 67]. The IL-6 elevation in postmenopausal women was reduced by estrogen replacement therapy [68]. The elevation of IL-6 may be related to free radical activities especially reactive oxygen species. Reactive oxygen species was found to elevate the IL-6 levels directly via activation of nuclear factor κB (NFκB) [69]. High cytokine levels would also result in activation of NFκB and promotion of osteoclastogenesis [70].

The effects of vitamin E on bone resorbing cytokines for prevention and treatment of osteoporosis have been studied using FeNTA and nicotine rat models [34, 71]. These models represent osteoporosis caused by oxidative stress and smoking, respectively. However, similar studies in humans are still lacking. Ferric nitrilotriacetate (FeNTA) is an oxidizing agent which produces free radicals via the Fenton reaction [72, 73]. Oxidative stress can be induced in rats by injecting them with FeNTA, allowing the hazardous effects of free radicals on various organs and tissues including bone to be studied. The bone resorbing cytokines, IL-1 and IL-6, were found to be elevated in this oxidative stress rat model, indicating inflammation. This was accompanied by osteoporotic changes as indicated by the measurement of bone markers and histomorphometric parameters [34]. The elevation of cytokines was probably achieved through the activation of cytokine-encoding genes like STAT3 or nuclear factor-kappaB by the free radicals [74, 75]. Therefore, there exist relationships between free radicals, inflammation, and bone loss which can lead to osteoporosis. When vitamin E in the form of tocotrienols and α-tocopherol were supplemented to these rats, IL-1 and IL-6 elevations were suppressed. Concurrent with this, the osteoporotic changes were also inhibited [34, 71, 76]. Therefore, there is a possibility that vitamin E, a potent antioxidant, has prevented free radicals from causing inflammation and osteoporosis. Tocotrienols seemed to be more superior than α-tocopherol in suppressing proinflammatory cytokines in the FeNTA rat model and in protecting their bone against osteoporosis [34]. Both the tocopherol and tocotrienol may have achieved this by scavenging the free radicals generated by FeNTA before they could activate the monocytes and osteoblasts, cells that produce IL-1 and IL-6.

Results from studies on cytokines have given us some insight on the mechanisms involved in the protection of vitamin E against osteoporosis. Free radicals are known to activate transcription factor NFκB which leads to the production of bone resorbing cytokines interleukin-1 and interleukin-6. These proinflammatory cytokines were believed to provide the link between inflammation and osteoporosis. Vitamin E may scavenge and neutralize free radicals before they could activate transcription factor NFκB. This was seen in an oxidative stress model (FeNTA model) in which vitamin E had reduced the levels of bone-resorbing cytokines [34]. Alternatively, vitamin E may have prevented the activation of NFκB by enhancing the internal antioxidative enzymes within the bone. This was demonstrated by Maniam et al. [92], whereby vitamin E supplementation reduced the femoral thiobarbituric acid-reactive substance (TBARS) and increased the glutathione peroxidase activity.

 

Source:

http://doi.org/10.1155/2012/142702

 

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