**Vitamin K2 Facilitating Inter-Organ Cross-Talk Vitamin K2 Facilitating Inter-Organ Cross-Talk**

Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller Gaute Floer Johnsen and Mona Møller Additional information is available at the end of the chapter

Jan O. Gordeladze, Håvard J. Haugen,

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67153

#### **Abstract**

regulation of the Cyp11a a cholesterol side chain cleavage enzyme in rats. Biochim.

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c1fo10058k.

198 Vitamin K2 - Vital for Health and Wellbeing

This chapter features how vitamin K2 is instrumental in bringing about inter-organ communication, thus facilitating (a) a synthesis/secretion of the endocrine, humoral factors from various organs and (b) physiological responses to the said factors by a multitude of organ systems of the body, thus creating a 'lattice' of reciprocal regulatory loops in order to ensure endocrine homeostasis.

**Keywords:** vitamin K2, MK-4, MK-7, PXR/SXR, FoxO and FoxA families of transcription factors, PI3K/Akt cascade, endocrine homeostasis, deiodinase (DIO2 ), NF-κB, interleukins, IGFs, MMPs, FGFs, irisin, osteonectin, UCP1, VEGF, GIP/GLP

**1. Introduction**

Recently, an abstract entitled 'Epigenetic factors involved in musculo-skeletal interaction - How skeletal muscle cells and osteoblasts derived from stem cells communicate with special reference to histone deacetylases (HDACS), transcription factors (TFs), microRNAs, and vitamin K2' was presented at an OMICS conference in Chicago, USA [1].

This work shows how the interactive axis consisting of 'Epigenator-Initiator-Maintainer' components determines the ultimate phenotypes of the cellular functions or the chain of reactions within different body organs and tissues. The initiator signals (i.e. histone modifications, phenotype modifications through transcriptional control, via microRNA species) constitute forces, slowly tilting the cell phenotype towards a more or less stable profile.

Despite this tendency, phenotypic characteristics could be subjected to alterations, that is, either weakened or reinforced, or even altered, resulting from underlying or developing diseases and/or gene therapy. The present work encompasses some data showing manipulations

of HDACs, transcription factors (TFs), as well as microRNAs and the impact of vitamin K2 (MK-7) on mineralizing cells (osteoblasts) and striated muscle cells exposed to either normal growth conditions or mediators of inflammation (i.e. Th-cells, macrophages, or interleukins), indicating that it is possible to engineer cells displaying an adapted phenotype where: (a) towards mineralization is reinforced, (b) untoward mineral deposition is halted and finally (c) mutual musculoskeletal interactions are 'reinforced'.

it was shown [4] that a lack of α-actinin-3 may lead to a reduction in bone mineral density

Vitamin K2 Facilitating Inter-Organ Cross-Talk

http://dx.doi.org/10.5772/67153

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PGC-1α seems to be instrumental in the modulation of mitochondrial biogenesis [5], and a further study established that PGC-1α elicited by physical activity seems to be crucial for oxidative metabolism in skeletal muscle fibres [6]. Furthermore, it was demonstrated that mitochondrial biogenesis induced by an enhancement in PGC-1α levels facilitates Wnt-mediated induction of osteoblastic differentiation of mesenchymal C3H10T1/2 cells [7]. These findings indicate that PGC-1α serves as a 'commitment' factor or inductor of stem cells to produce osteoblastic cells. Another essential factor is MEF-2C, which interacts with other myogenic regulatory factors, like Myf5 and MyoD, which in a synergistic fashion activates specific muscle-phenotypic genes. Animals devoid of MEF-2C in osteocytes make less sclerostin, a humoral factor acting as an inhibitor of the Wnt family of signalling molecules involved in osteoblast differentiation and bone formation. Thus, the MEF-2C-sclerostin signalling inhibits the formation of excessive

bone mass and a 'healthy' turnover, which normally ensures minimal bone brittleness.

Qiu et al. [8] demonstrates that NF-κb-mediated signalling modulates myostatin transcription in myoblasts during cirrhosis-induced hyperammonaemia. This suggests that NF-κB antagonists are useful to reverse cirrhosis induced by sarcopenia. This observation also indicates that vitamin K2-induced modulation of NF-κB may determine the levels of humoral factors, which reciprocally regulate muscle and bone physiology. We have found [Gordeladze et al., 2015, unpublished] that preadipocytes, with mutated and superactive Gsα-induced adenylate cyclase activity, in the presence of vitamin K2 (MK-7), produce more beige-like adipocytes (see **Figure 1**) than large white adipocytes (ref), with an enhancement in PGC-1α levels (ref). Hence, it may be asserted that vitamin K2 facilitates Wnt-mediated induction of osteoblastic differentiation by

**Figure 1.** Putative working model showing how vitamin K2 may affect the hormonal signalling systems and transcription factors responsible for the transition of «white» adipocytes to «beige» adipocytes, thus blocking fat deposition and

(BMD) in both humans and rodents.

enhancing the production of heat from fatty acids.

With the aid of various algorithms, one may reveal regulatory loops involving both TFs and microRNAs. The subjects TFs and microRNA species appeared to be part of an intricate hierarchical structure encompassing several classes of HDACs, including the Sirtuins, known to respond to cellular energy status (i.e. NADH/NAD+ ratios). Finally, it was demonstrated that vitamin K2 (MK-7, via binding to the transcription factor SXR) interfered with a plethora of signalling pathways (such as the FoxA and FoxO families of transcription factors), the downstream of the signalling mechanisms represented by the PI3-kinase system (i.e. Akt/PKB and SGK, respectively), thus potentiating the cross-talk signals or suppressing the mineralizing character. It was concluded that vitamin K2 plays a pivotal role by optimizing the endocrine interaction between osteoblasts and striated muscle cells, facilitating a 'win-win' situation. Furthermore, we have shown that vitamin K2 may confer the ability for cross-talk between striated muscle cells and bones to include cells, such as insulin-producing β-cells, thyroid follicular cells, PTH-producing parathyroid cells and hepatocytes, in the absence or presence of inflammatory cells or their secreted cytokines/interleukins ± TNFα.

Sarcopenia (reduced muscle mass and/or function) and osteoporosis (bone brittleness) have generally been known for their relations to the locomotive syndrome and are linked to old age. Contrastingly, an increased muscle mass correlates with an enhanced bone mass and thus with a reduced fracture incidence. Genetic, as well as endocrine and mechanical factors, inflammation and nutritional states concurrently impinge on muscle tissue and bone metabolism.

Furthermore, a plethora of genes like myostatin and α-actinin-3 associate with both conditions. Factors such as vitamin D, growth hormones (like GH and IGF-1) and testosterone and pathological conditions with excess cortisol, as well as type I diabetes (T1DM), affect both muscle and bone tissues. It was shown that the genes Tmem119, osteoglycin and FAM5C may be critical for the commitment of myoprogenitor cells to the osteoblast lineage. Furthermore, osteoglycin and FAM5C might serve as muscle-derived humoral osteogenic factors. Others, encompassing myostatin, osteonectin, as well as IGF-1, irisin and osteocalcin, may also be associated with reciprocal metabolic interactions between muscle and bone [2].
