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

Abstract

Vitamin K 2 is a critical nutrient required for blood clotting that also plays an important role in bone formation. Vitamin K 2 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 K 2 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 K 2 also has a transcriptional regulatory function. Vitamin K 2 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 K 2 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 K 2 . Vitamin K 2 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 K 2 is a transcriptional regulator of bonespecific 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.

Additive Effect of Vitamin K2 and Risedronate on Long Bone Mass in Hypophysectomized Young Rats

“…Regulation of bone formation by vitamin K 2 may involve the γ-carboxylation of osteocalcin or may be mediated via the steroid and xenobiotic receptor (SXR) [13,27,[34][35][36]. However, it has also been reported that vitamin K 2 inhibits bone resorption via a mechanism that is independent of γ-carboxylation and related to its side chain [11].…”

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

“…The role of TERE1 in vitamin K-2, menaquinone, synthesis (Nakagawa et al, 2010) provides a highly probable and established mechanism of TERE1-mediated cholesterol modulation. Menaquinone is a known ligand for the nuclear receptor SXR (Tabb et al, 2003;Shearer and Newman, 2008;Zhou et al, 2009). SXR is known to heterodimerize with RXR and cross regulate LXR target genes that have wellestablished roles in modulation of cellular cholesterol efflux (Landes et al, 2003;Sonoda et al, 2005;Wang and Rader, 2007;Wang et al, , 2008bLim and Huang, 2008;Brown and Jessup, 2009;Zhou et al, 2009).…”

Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification

“…In feeding studies Spronk et al (16) showed that MK4 but not vitamin K 1 could prevent arterial calcification in rats when given in combination with warfarin. Certain combinations of vitamin K and warfarin given to rodents have been shown to inhibit vitamin K-dependent γ-carboxylation in extrahepatic tissues but not in the liver which maintains a normal coagulation system (18). As reduced vitamin K 1 and reduced MK4 are both cofactors in the γ-carboxylation system, this finding has raised questions about additional effects of MK4 in the arterial wall which may enhance inhibition of arterial calcification.…”