Vitamin K2 stimulates osteoblastogenesis and suppresses osteoclastogenesis by suppressing NF-κB activation

Int J Mol Med. 2011 Jan;27(1):3-14. doi: 10.3892/ijmm.2010.562. Epub 2010 Nov 11.

Abstract

Several bone protective factors are reported to exhibit stimulatory activities on bone formation coupled with inhibitory effects on bone resorption; one such factor is vitamin K2. Vitamin K species [K1 (phylloquinone) and K2 (menaquinone)] have long been associated with bone protective activities and are receiving intense interest as nutritional supplements for the prevention or amelioration of bone disease in humans. However, the mechanisms of vitamin K action on the skeleton are poorly defined. Activation of the nuclear factor κB (NF-κB) signal transduction pathway is essential for osteoclast formation and resorption. By contrast, NF-κB signaling potently antagonizes osteoblast differentiation and function, prompting us to speculate that NF-κB antagonists may represent a novel class of dual anti-catabolic and pro-anabolic agents. We now show that vitamin K2 action on osteoblast and osteoclast formation and activity is accomplished by down-regulating basal and cytokine-induced NF-κB activation, by increasing IκB mRNA, in a γ-carboxylation-independent manner. Furthermore, vitamin K2 prevented repression by tumor necrosis factor α (TNFα) of SMAD signaling induced by either transforming growth factor ß (TGFß) or bone morphogenetic protein-2 (BMP-2). Vitamin K2 further antagonized receptor activator of NF-κB (RANK) ligand (RANKL)-induced NF-κB activation in osteoclast precursors. Our data provide a novel mechanism to explain the dual pro-anabolic and anti-catabolic activities of vitamin K2, and may further support the concept that pharmacological modulation of NF-κB signal transduction may constitute an effective mechanism for ameliorating pathological bone loss and for promoting bone health.

MeSH terms

  • 3T3 Cells
  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / physiology
  • Bone Morphogenetic Protein 2 / metabolism
  • Bone Resorption
  • Cell Differentiation / drug effects*
  • Female
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Osteoblasts / cytology
  • Osteoblasts / drug effects*
  • Osteoblasts / physiology*
  • Osteoclasts / cytology
  • Osteoclasts / drug effects*
  • Osteoclasts / physiology*
  • Osteogenesis / drug effects
  • Osteogenesis / physiology
  • RANK Ligand / pharmacology
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism
  • Stromal Cells / cytology
  • Stromal Cells / drug effects
  • Stromal Cells / physiology
  • Transforming Growth Factor beta / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vitamin K 2 / analogs & derivatives
  • Vitamin K 2 / pharmacology*
  • Vitamins / pharmacology

Substances

  • Bone Morphogenetic Protein 2
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • RANK Ligand
  • Smad Proteins
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Vitamins
  • Vitamin K 2
  • NF-KappaB Inhibitor alpha
  • vitamin MK 7