The Two Sides of Vitamin E Supplementation.

Vitamin E is a lipid-soluble antioxidant that inhibits lipid peroxidation by scavenging reactive oxygen species, and it is thought to protect against the aging process. Indeed, it is one of the most popular supplements in the US. However, recent studies have revealed that vitamin E has dual effects on the aging process. We discovered that α-tocopherol, the major form of vitamin E in the body, stimulates osteoclast fusion and bone resorption as well as induces an osteoporosis-like phenotype in rodents. Clinical intervention trials have also demonstrated that supplementation with vitamin E is neutral or even harmful for preventing age-related diseases in humans. Therefore, the role of vitamin E as an 'anti-ager' has been called into question. This review outlines the present understanding of the role of vitamin E in age-related disease prevention.

Vitamin E decreases bone mass by stimulating osteoclast fusion.

Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption. Osteoclasts are multinucleated cells that are formed by mononuclear preosteoclast fusion. Fat-soluble vitamins such as vitamin D are pivotal in maintaining skeletal integrity. However, the role of vitamin E in bone remodeling is unknown. Here, we show that mice deficient in α-tocopherol transfer protein (Ttpa(-/-) mice), a mouse model of genetic vitamin E deficiency, have high bone mass as a result of a decrease in bone resorption. Cell-based assays indicated that α-tocopherol stimulated osteoclast fusion, independent of its antioxidant capacity, by inducing the expression of dendritic-cell-specific transmembrane protein, an essential molecule for osteoclast fusion, through activation of mitogen-activated protein kinase 14 (p38) and microphthalmia-associated transcription factor, as well as its direct recruitment to the Tm7sf4 (a gene encoding DC-STAMP) promoter. Indeed, the bone abnormality seen in Ttpa(-/-) mice was rescued by a Tm7sf4 transgene. Moreover, wild-type mice or rats fed an α-tocopherol-supplemented diet, which contains a comparable amount of α-tocopherol to supplements consumed by many people, lost bone mass. These results show that serum vitamin E is a determinant of bone mass through its regulation of osteoclast fusion.

[Hormones and osteoporosis update. Regulation of bone remodeling by neuropeptides and neurotransmitters].

From the discovery of the regulation of bone remodelling by leptin, much attention has been focused on neurogenic control of bone remodelling. Various hypothalamic neuropeptides, which are involved in appetite regulation, are now revealed to be important regulators of bone remodelling. More recently, neurotransmitters, such as serotonin or catecholamines, are proven to be bone remodelling regulators.

Molecular bases of the sympathetic regulation of bone mass.

The discovery that leptin regulates bone mass through a central relay generated a lot of interest and raised the question about the identity of the neural mediator linking the brain to the skeleton. In this review we discuss the genetic, neuroanatomical and physiological evidence identifying the sympathetic tone as one of the mediator of leptin regulation of bone mass. We also discussed the antagonistic role played by two beta adrenergic receptors in this regulation and the relevance of these results obtained through studies of model organisms to human physiology and pathology.

Central control of bone remodeling.

The hormonal control of osteoblast activity has been speculated for a long time. In search of such a central hormone, leptin was identified as an inhibitor of bone formation. Intracerebroventricular infusion of leptin resulted in a decrease of bone mass establishing that bone mass is regulated centrally. The peripheral mediator of leptin's action was identified as being the sympathetic nervous system. Mice deficient for catecholamines have high bone mass. beta-Receptor agonists decreased bone mass, and conversely, treatment by beta-blockers increased bone mass.

Leptin regulates bone formation via the sympathetic nervous system.

We previously showed that leptin inhibits bone formation by an undefined mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function do not affect bone formation. Leptin deficiency results in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreases bone mass in leptin-deficient and wild-type mice while a beta-adrenergic antagonist increases bone mass in wild-type and ovariectomized mice. None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.