Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR.
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 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 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.
Tabb
Michelle M
MM
Department of Developmental and Cell Biology, University of California, Irvine, California 92697-2300, USA.
Sun
Aixu
A
Zhou
Changcheng
C
Grün
Felix
F
Errandi
Jody
J
Romero
Kimberly
K
Pham
Hang
H
Inoue
Satoshi
S
Mallick
Shyamali
S
Lin
Min
M
Forman
Barry M
BM
Blumberg
Bruce
B
D000469:Alkaline Phosphatase / Q000032:analysis / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds; D019556:COS Cells; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000737:chemistry; D015675:Osteocalcin / Q000235:genetics; D053495:Osteopontin; D053244:Osteoprotegerin; D012516:Osteosarcoma / Q000737:chemistry; D010696:Phloroglucinol / Q000031:analogs & derivatives; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011987:Receptors, Steroid / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012293:Rifampin / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000235:genetics; D013729:Terpenes / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D024482:Vitamin K 2 / Q000378:metabolism / Q000494:pharmacology*
D015415:Biomarkers; D001643:Bridged Bicyclo Compounds; D006023:Glycoproteins; D053244:Osteoprotegerin; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; C506030:TNFRSF11B protein, human; D013729:Terpenes; C506031:Tnfrsf11b protein, mouse; D015675:Osteocalcin; D053495:Osteopontin; D024482:Vitamin K 2; D003577:Cytochrome P-450 Enzyme System; D010696:Phloroglucinol; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000469:Alkaline Phosphatase; C001654:hyperforin; D012293:Rifampin