Endocrine Abstracts

Vitamin K is known as a critical cofactor in blood coagulation and bone homeostasis by helping the function of vitamin K-dependent gamma-carboxylase. We have recently shown that vitamin K2, one of the natural vitamin Ks, has a novel function to regulate the transcription of extracellular matrix-related genes in osteoblastic cells and increase collagen accumulation by activating the steroid and xenobiotic receptor, SXR. In the present study, we searched for novel vitamin K target genes up-regulated specifically by menaquinone-4 (MK-4), a potent vitamin K2 isoform, using oligonucleotide microarray analysis in human osteoblastic MG63 cells. Among these genes, growth differentiation factor (GDF15) and stanniocalcin 2 (STC2) were characterized as MK-4-specific targets, as their mRNA expression was not induced by vitamin K1, another vitamin K2 isoform MK-7, or the MK-4 side chain structure geranylgeraniol. The MK-4-specific induction of GDF15 and STC2 was also observed in murine MC3T3-E1 cells and shown to be independent of either gamma-carboxylation or SXR signaling. As a possible mechanism for MK-4-specific gene regulation, we investigated the contribution of protein kinase A (PKA), one of the key regulators of transcription in osteoblasts. We found that MK-4 enhanced PKA phosphorylation, and the MK-4-specific induction of GDF15 and STC2 genes was reduced by treatment with the PKA inhibitor H89 or siRNA against PKA alpha-catalytic subunit. In conclusion, vitamin K2 has novel functions beside its activity as a coenzyme and plays a significant role in regulating various gene expression and modulating collagen production in osteoblastic cells.