Break a Bone

Science Signaling  10 Apr 2012:
Vol. 5, Issue 219, pp. ec104
DOI: 10.1126/scisignal.2003117

Vitamin E is a lipid-soluble antioxidant that is predominantly biologically available as α-tocopherol. Vitamin E supplements are frequently consumed because of their reported beneficial effects on the cardiovascular system (see Roodman); however, different studies have shown beneficial or deleterious effects on bone homeostasis. Ttpa−/− mice are a genetic model for vitamin E deficiency because they lack α-tocopherol transfer protein (α-TTP), a liver protein that helps to recycle α-tocopherol from plasma. Fujita et al. found that, compared with wild-type mice, Ttpa−/− mice had greater bone mass because of lower bone resorption, rather than increased bone formation. Treatment of bone marrow cells from wild-type mice with α-tocopherol increased their differentiation into osteoclasts (cells that mediate bone resorption) without affecting their differentiation into osteoblasts (cells that mediate bone formation). α-tocopherol promoted osteoclast fusion (which occurs late in osteoclast maturation), an effect that was mediated by increased expression of the gene encoding dendritic-cell–specific transmembrane protein (DC-STAMP), a receptor that is required for osteoclast fusion, rather than the antioxidant properties of α-tocopherol. Treatment of bone marrow cells with α-tocopherol activated the mitogen-activated protein kinase (MAPK) p38α and its upstream kinases mitogen-activated protein kinase kinases 3 and 6 (MKK3/6). p38α phosphorylated and activated microphthalmia-associated transcription factor (MITF), which is required for osteoclast development and bound to the promoter of the gene encoding DC-STAMP. Wild-type mice that received α-tocopherol at concentrations comparable to those in human dietary supplements showed decreased bone mass, which correlated with increased bone resorption and osteoclast size. Thus, individuals who consume vitamin E supplements could be at increased risk for bone loss.

K. Fujita, M. Iwasaki, H. Ochi, T. Fukuda, C. Ma, T. Miyamoto, K. Takitani, T. Negishi-Koga, S. Sunamura, T. Kodama, H. Takayanagi, H. Tamai, S. Kato, H. Arai, K. Shinomiya, H. Itoh, A. Okawa, S. Takeda, Vitamin E decreases bone mass by stimulating osteoclast fusion. Nat. Med. 18, 589–594 (2012). [Online Journal]

G. D. Roodman, Vitamin E: Good for the heart, bad for the bones? Nat. Med. 18, 491–492 (2012). [Online Journal]