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J. Biol. Chem., Vol. 278, Issue 45, 43919-43927, November 7, 2003

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Vitamin K₂ Regulation of Bone Homeostasis Is Mediated by the Steroid and Xenobiotic Receptor SXR^*

Michelle M. Tabb, Aixu Sun, Changcheng Zhou, Felix Grün, Jody Errandi, Kimberly Romero, Hang Pham, Satoshi Inoue, Shyamali Mallick¶, Min Lin¶, Barry M. Forman¶, and Bruce Blumberg||

From the Department of Developmental and Cell Biology, University of California, Irvine, California 92697-2300, the Department of Geriatric Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, and the ^¶Division of Molecular Medicine, Gonda Diabetes Research Center, Beckman Research Institute, The City of Hope National Medical Center, Duarte, California 91010-3000

Vitamin K₂ is a critical nutrient required for blood clotting that also plays an important role in bone formation. Vitamin K₂ supplementation up-regulates the expression of bone markers, increases bone density in vivo, and is used clinically in the management of osteoporosis. The mechanism of vitamin K₂ action in bone formation was thought to involve its normal role as an essential cofactor for -carboxylation of bone matrix proteins. However, there is evidence that suggests vitamin K₂ also has a transcriptional regulatory function. Vitamin K₂ bound to and activated the orphan nuclear receptor SXR and induced expression of the SXR target gene, CYP3A4, identifying it as a bona fide SXR ligand. Vitamin K₂ treatment of osteosarcoma cells increased mRNA levels for the osteoblast markers bone alkaline phosphatase, osteoprotegerin, osteopontin, and matrix Gla protein. The known SXR activators rifampicin and hyperforin induced this panel of bone markers to an extent similar to vitamin K₂. Vitamin K₂ was able to induce bone markers in primary osteocytes isolated from wild-type murine calvaria but not in cells isolated from mice deficient in the SXR ortholog PXR. We infer that vitamin K₂ is a transcriptional regulator of bone-specific genes that acts through SXR to favor the expression of osteoblastic markers. Thus, SXR has a novel role as a mediator of bone homeostasis in addition to its role as a xenobiotic sensor. An important implication of this work is that a subset of SXR activators may function as effective therapeutic agents for the management of osteoporosis.

Received for publication, March 26, 2003 , and in revised form, July 27, 2003.

^* This work was supported by National Cancer Institute Grant CA-87222, National Institutes of Health Grant GM-60572, and a gift from Eisai Co., Ltd. Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Developmental and Cell Biology, University of California, 5205 McGaugh Hall, Irvine, CA 92697-2300. Tel.: 949-824-8573; Fax: 949-824-4709; E-mail: blumberg{at}uci.edu.

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