The Dual Role of Vitamin K2 in "Bone-Vascular Crosstalk": Opposite Effects on Bone Loss and Vascular Calcification

Abstract

Osteoporosis (OP) and vascular calcification (VC) represent relevant health problems that frequently coexist in the elderly population. Traditionally, they have been considered independent processes, and mainly age-related. However, an increasing number of studies have reported their possible direct correlation, commonly defined as "bone-vascular crosstalk". Vitamin K2 (VitK2), a family of several natural isoforms also known as menaquinones (MK), has recently received particular attention for its role in maintaining calcium homeostasis. In particular, VitK2 deficiency seems to be responsible of the so-called "calcium paradox" phenomenon, characterized by low calcium deposition in the bone and its accumulation in the vessel wall. Since these events may have important clinical consequences, and the role of VitK2 in bone-vascular crosstalk has only partially been explained, this review focuses on its effects on the bone and vascular system by providing a more recent literature update. Overall, the findings reported here propose the VitK2 family as natural bioactive molecules that could be able to play an important role in the prevention of bone loss and vascular calcification, thus encouraging further in-depth studies to achieve its use as a dietary food supplement.

Keywords: calcium paradox; menaquinone; osteoporosis; vascular calcification; vitamin K2.

Figure 1

Molecular structure of the two main forms of Vitamin K. The upper structure represents Vitamin K1, also known as phylloquinone. The bottom structure is Vitamin K2, also known as menaquinone (MK).

Figure 2

Mechanisms of action of VitK2 in “bone and vascular cross-talk”. At vascular level, VitK2, acting as cofactor for the enzyme GGCX, triggers the conversion of undercarboxylated MGP (ucMGP) in active carboxylated MGP (cMGP). The active cMGP could directly inhibit ectopic Ca2+ precipitation, but also VSMCst trans-differentiation through BMP-2. VitK2 can also inhibit VSMCs apoptosis through the Gas6/ AxL/Akt anti-apoptotic pathway. In bone tissue, VitK2 could promote osteoblasts proliferation and activity through MGP and Wnt/β-catenin pathway, control of oxidative stress (Ox-S) imbalance, via SXR receptor, and the well-established GGCX-dependent pathway. VitK2 may also exert a control of osteoclasts activities through the inhibition of NF-kB.