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Papers In Press, published online ahead of print August 14, 2003
Department of Developmental & Cell Biology, University of California Irvine, Irvine, CA 92697-2300
Corresponding Author: blumberg{at}uci.edu
Vitamin K2 is a critical nutrient required for blood clotting that also plays an important role in bone formation. Vitamin K2 supplementation upregulates 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 gamma-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 a similar extent as did 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.
J. Biol. Chem, 10.1074/jbc.M303136200
Submitted on March 26, 2003
Revised on July 27, 2003
Accepted on August 14, 2003
Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor, SXR
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