Vitamin K2 is a critical nutrient required for blood coagulation. It also plays 
a key role in bone homeostasis and is a clinically effective therapeutic agent 
for osteoporosis. We previously demonstrated that vitamin K2 is a 
transcriptional regulator of bone marker genes in osteoblastic cells and that it 
may potentiate bone formation by activating the steroid and xenobiotic receptor, 
SXR. To explore the SXR-mediated vitamin K2 signaling network in bone 
homeostasis, we identified genes up-regulated by both vitamin K2 and the 
prototypical SXR ligand, rifampicin, in osteoblastic cells using oligonucleotide 
microarray analysis and quantitative reverse transcription-PCR. Fourteen genes 
were up-regulated by both ligands. Among these, tsukushi, matrilin-2, and CD14 
antigen were shown to be primary SXR target genes. Moreover, collagen 
accumulation in osteoblastic MG63 cells was enhanced by vitamin K2 treatment. 
Gain- and loss-of-function analyses showed that the small leucine-rich 
proteoglycan, tsukushi, contributes to vitamin K2-mediated enhancement of 
collagen accumulation. Our results suggest a new function for vitamin K2 in bone 
formation as a transcriptional regulator of extracellular matrix-related genes, 
that are involved in the collagen assembly.