MiRNAs Expression Modulates Osteogenesis in Response to Nutrition: History
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Contributor:
Patrizia Proia
,
Carlo Rossi
,
Anna Alioto
,
Alessandra Amato
,
Caterina Polizzotto
,
Andrea Pagliaro
,
Szymon Kuliś
,
Sara Baldassano

Epigenetic mechanisms may influence gene activity at the transcriptional and post-transcriptional levels. Among the most studied epigenetic modifications, there are changes in the expression profile of microRNAs (miRNAs or miRs). Furthermore, it is already known that diet along with exercise, can modulate the expression of endogenous miRNAs and prevent or delay the development of some metabolic diseases such as bone disorders, confirming the importance of epigenetics in bone regeneration. In addition, some foods contain miRNAs that after ingestion can influence the various biological processes. The bone tissue is metabolically active and it is constantly remodelling in response to different stimuli. MiRNAs expression together with specific transcription factors control the differentiation of the mesenchymal cells from which the osteogenic line cells originate. 

  • nutrition
  • macro- and micronutrients
  • bone health
  • exercise
  • exogenous and endogenous miRNAs
  • epigenetics

1. Exercise and Osteogenic MicroRNAs Expression

Bone tissue is a tissue that is sensitive to mechanical stimuli. Mechanical loads, including compression and deformation, are the stimuli that play essential roles in the differentiation and mineralization of osteoblasts, as well as maintaining high bone mass and density decreasing the risk of osteoporosis [1]. Some studies show that high-impact exercise increases bone mineral density (BMD) [2][3][4][5]. The load applied to the bone must always be gradual and administered considering the age of the subject and eventually, the pathologies that are in place. However, an in vitro experiment performed on osteoclast indicates that mechanical stimulus increases the expression of some miRNAs; these mechanisms could be considered important therapeutic candidates for the prevention and treatment of bone diseases, in particular for osteoporosis [6][7]. Recently, it has been shown that the half marathon increases the expression of miR-21-5p that promotes the proliferation of mesenchymal stem cells by targeting the two antagonists of the Transforming growth factor β (TGFb) pathway: Phosphatase and tensin homologue (PTEN) and Small mother against decapentaplegic 7 (Smad7) by reducing their expression. PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway via lipid phosphatase activity and controls different cellular processes including survival, proliferation, energy metabolism, and cellular architecture [8]. TGFb is a pleiotropic cytokine that regulates many processes such as cell growth, differentiation, apoptosis, migration, and immune response. Smad7 is a TGF-β/Smad signal antagonist and is a negative regulator of Runt-related transcription factor 2 (RUNX2); it reduces PTEN expression, accelerates osteoblast differentiation and increases cell survival through PI3K/Akt signalling [2][9]. In fact, in vitro, PTEN-deficient osteoblasts proliferate faster by reducing apoptosis and increasing the cell size; this is consistent with the effects of activation of Akt and mTOR pathways [10]. Reduced expression of PTEN and SMAD7 induced an increase in the AKT/pAKT and SMAD4 protein levels, and this overregulates RUNX2 gene expression [2].
In addition, it has been seen that the proliferative potential of mesenchymal stem cells decreases with age due to the telomere shortening. During cellular division, it is possible to have a greater decrease in telomeres, with a consequent loss of genetic information, therefore an aging process that leads to cell death. Telomere length is therefore important to counteract the senescence of mesenchymal stem cells and telomerase plays an important role in this regard and in promoting the differentiation process [11]. Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA sequences and provides the molecular basis for unlimited proliferative potential [12]. Oxidative stress in response to exercise increases the expression of the human telomerase reverse transcriptase gene (hTERT) in human marrow stromal cells (hMSC), increasing telomerase activity that promotes osteoblast differentiation [13].
Hua-Yu Zhu et al. have shown that the same miR-21 can regulate hTERT via PTEN in different processes [14]. Telomerase has also been reported to regulate autophagy with an important role in the differentiation and regulation of stem cells of various cell types, including mesenchymal stem cells [15]. The increased expression of telomerase may be due to oxidative stress resulting from physical activity. Autophagy would appear to be involved in the regulation of the cellular redox state induced by physical activity through the degradation of iron-binding proteins such as ferritin [15].
Furthermore, it is already known that resistance exercise induces an increase in iron levels, probably related to tissue damage. Excess iron is considered toxic precisely because of its ability to accept and donate electrons and to be involved in the reaction called “The Fenton reaction”, in which reacting with hydrogen peroxide generates both hydroxyl radicals and higher oxidation states of the iron evolving into free radicals [16][17].
The increase in osteogenesis-related genes expression following physical exercises such as RUNX2, muscle segment homeobox 1 (MSX1) and secreted phosphoprotein (SPP1) act to increase the expression of hTERT and telomere repeat binding factor 1 (TERF1), indicates the activity of mesenchymal stem cells and their increased capability to differentiate [13].

2. Micronutrients Intake and Osteogenic MicroRNAs Expression

Nutrients can interact directly with the genome and indirectly through modulation of mechanisms, including DNA methylation, histone modification and non-coding RNA expression, in particular the miRNAs. Vitamins and minerals can induce the expression of miRNAs through the activation of transcription factors, which regulate the gene expression by induction of messenger RNA (mRNA) degradation or inhibit their translation. They can also modify the expression of DNA methyltransferases (DNMT) and different enzymes such as histone deacetylase and histone acetyltransferase that are involved in several processes such as transcription activation, gene silencing, DNA repair and cell cycle progression [18]. DNMT would appear to prevent demethylation in postmitotic neurons, which together with DNA methylation provide an epigenetic mechanism of gene regulation in neural development, function and disorders [19]. The modulation of the activity of these enzymes leads to changes in the methylation state of DNA as well as the histones, which in turn modulate the expression of some genes, including the miRNAs themselves.

2.1. Vitamin D Intakes

Among the micronutrients, vitamin D plays a key role in promoting bone mineralization [20][21][22], facilitating the intestinal absorption of phosphorus and calcium intake with the diet that is involved in bone calcification. Vitamin D is a member of the steroid hormones families with nuclear steroid receptors (NR) signalling function and is involved in the biogenesis and regulation of miRNAs expression [20][23]. It is already known that oestrogens have fundamental anticatabolic and anabolic effects on bones; therefore, the lack of oestrogen plays a central role in the development of osteoporosis [24][25]. The active form, 1,25 dihydroxy vitamin D (1,25(OH)2 D), can regulate the expression of osteoblastic mineralization factors by affecting the expression of some specific miRNAs like miR-637 and miR-1228. The miR-637 would seem to act by degrading the mRNA of Collagen Type IV α 1 Chain (COL4A1), whose expression, during osteoblastic differentiation, inhibits matrix mineralization; while miR-1228, is a mirtron, an alternative precursor for microRNA biogenesis that was recently described in invertebrates, that uses a different mechanism of action than classical miRNAs, as they bypass the cleavage of enzyme DROSHA, is exported out of the nucleus, split by endoribonuclease Dicer and incorporated into the RISC [26]. The miR-1228 reduces the expression of the Bone Morphogenetic Protein 2 (BMP2K) inducible kinase, a protein potentially implicated in cellular endocytosis and differentiation, but its molecular functions have remained unknown; it seems to be a potent inducer of bone formation through its stimulation of osteoblast differentiation [20]. Given the importance of vitamin D, it is therefore very important to guarantee high levels, which can be achieved through diet, such as cholecalciferol, thanks to animal foods intake such as salmon and blue fish or mackerel or cod liver oil consumed mainly as a supplement. Another source of vitamin D is vitamin D2 or ergocalciferol, which is a bit less active, but of which plant-based food is rich, for example, mushrooms. In any case, 80% of the vitamin D needed is guaranteed by sun exposure. Therefore, the best practice to increase vitamin D levels is to carry out physical exercise outdoors to guarantee good production and positive action also on bone metabolism [2][3].

2.2. Vitamin C Intakes

Even vitamin C plays a positive role in bone health; in fact, it is a cofactor in multiple biological processes such as collagen synthesis and antioxidant capability, regulating stem cell differentiation and improving osteoblast activity [23][27][28]. Clinical studies performed in humans and animals have shown that a deficiency of vitamin C leads to musculoskeletal alterations; noteworthy, the results showed that 100 mM of vitamin C effectively activates genes related to the musculoskeletal system in BMSCs, whilst lower doses, 25 mM, did not induce any effect. Similar results have also been observed for the regulation of vitamin C-dependent miRNAs production [27][29]. There is a possibility that vitamin C treatments regulate miR-29b-1 and miR-589-5p expression by promoting Octamer-binding transcription factor ¾ (Oct3/4), Nanog, sex-determining region Y-box 2 (SOX2) and Mitogen-Activated Protein Kinase Kinase Kinase 8 (MAP3K8) expressions in BMSCs contributing to cell proliferation and differentiation. In addition, it increases the expression of miR-371b-5p, miR-181a and miR-215 in BMSCs. The study hypothesis would be that these miRNAs, respectively, promote cell proliferation and differentiation of these cells [27][30][31].

2.3. Orthosilicic Acid (OSA) Intakes

Among the various micronutrients that contribute to bone health is also orthosilicic acid (OSA), which stimulates osteoblastic differentiation. Studies on ovariectomized rats orthosilicic acid fed compared to other deprived rats showed a higher bone mineral density (BMD) and trabecular thickness. Recently, it has been discovered that miR-130b plays a role in cell proliferation, differentiation, and apoptosis; its expression increased during the osteogenic differentiation of multipotent mesenchymal stem cells of the human bone marrow. The study provided by Yunhao You et al. found an increase in his level during osteogenesis in response to 20 mM of orthosilicic acid and suggested that overexpression of miR-130b promoted osteogenic differentiation. However, the mechanisms of action, which promote his transcription, have yet to be explored. Nutrition can contribute to the intake of OSA. Indeed, its absorption is more effective if taken from the liquid phase in which it is dissolved and easily assimilated not having to undergo major changes [32]. Regular mineral water contains about 6.8 mg per litre, but there is some water whose silicon content can range from 14.4 mg up to 60 mg per litre. In food it is mainly contained in the leathery parts of vegetables; for this reason, it is important to consume vegetables and fruits with peel and legumes and prefer foods that have undergone few industrial processes to preserve their structure and content.

2.4. Other Micronutrients Intakes

Recent studies suggest that other micronutrients, such as natural phenolic acids, usually found in plants that are commonly intake by diet, may have an important bone anti-resorption activity [33][34][35]. One of these compounds is syringic acid, 3,5-dimethoxy-4-hydroxybenzoic acid (SA), a phenolic acid that acts on mouse mesenchymal stem cells (mMSC) cells inducing the differentiation of osteoblasts. It increases miR-21 expression, which reduces Smad7 activity by targeting the TGF-b/BMP signalling pathway, resulting in increased RUNX2 expression, thus leading to the expression of osteoblast differentiation markers genes such as alkaline phosphatase (ALP), Collagen Type I α 1 (Col-I) and osteocalcin (OCN) in BMSCs [36]. Also, isoflavones, i.e., syringe, genistein, laminarin, hesperetin and sulphurin, promote osteoblast differentiation through activation of the BMP2/SMAD5/Akt/RUNX2 pathway [37]. Deep SA has several positive effects on bone health due to its strong antioxidant activity and also through antihypertensive, antiproliferative, antiendotoxic, antitumor, hepatoprotective and antihyperglycemic effects. It is mainly present in olives, walnuts and dates, but also in blue-coloured fruits and berries, where it is formed by the decomposition of lenin, an anthocyanin, and its aglycone, malvidin [38]. This justifies its presence in red wine (0.27 mg/100 mL) and red vinegar (0.30 mg/100 mL) whilst in dried fruits such as walnuts or peanuts as well as in olives, cocoa pulp, pumpkin, durum wheat and in smaller quantities in peas and cauliflower, the concentration can reach 33 mg/100 g [32].

3. Macronutrients Intake and Osteogenic MicroRNAs Expression

Macronutrients influence important signalling pathways that regulate human metabolism [39]. However, it is not effortless to discriminate whether a nutrition–gene interaction is the result of a direct or indirect effect due to the involvement of several bioactive components. In other words, nutrients can induce epigenetic changes, either through methylation of DNA or changes in some miRNAs expression. Carbohydrates or Carbs (CHO), proteins and fats are broken down during digestion into the composition monomers respectively monosaccharides, amino acids and fatty acids [40][41]. Few studies have been carried out on the role of carbs and lipids on bone health. Currently, Kang Gan et al. investigated the roles of miR-221-3p and miR-222-3p, in regulating the osteogenic differentiation of BMSCs under high blood glucose conditions. The results showed increased expression of these two miRNAs in the bone tissue of diabetic mice, inhibiting osteogenic differentiation via the IGF-1/ERK pathway activation [42]. Further studies showed that high blood glucose levels, together with increased free fatty acids (FFA), increased the expression of miR-449, which inhibits osteogenic differentiation of BMSCs through suppression of the Sirt1/Fra-1 (Fos-related antigen) pathway [43]. MiR-449 directly targets sirtuin 1 (Sirt1) of the SIRT family by binding the 3′-UTR sequence. Sirt1 belongs to the NAD+-dependent enzymes classes that catalyse the deacylation of acyl-lysine residues that regulate the life span of mammals, cellular energy metabolism and the balance between osteoclastic and osteoblastic activity through different signalling pathways [44]. A study reported that Sirt-1 activated by resveratrol (a flavonoid) inhibits osteoclastogenesis; also 1 Fra-1, a protein belonging to the activator protein 1 (AP-1) family of transcription factors, plays an essential role in osteogenesis. Increased expression of miR-449, also significantly reduced mRNA and protein expression levels of osteogenic-differentiation-related marker genes, including RUNX2, bone sialoprotein (BSP), collagen I, and OCN. The latter regulates bone mineralization and bone turnover in the late stages of osteoblast differentiation, whilst BSP is involved in the mineralization [43].
Some studies suggest that a diet containing low amounts of methionine (belonging to the sulfur amino acids, SAAs) increases the expression of the miRNAs that alter RUNX2 expression by altering bone structure in mice. This is important because the methionine cycle generates S-adenosyl methionine (SAM), a coenzyme used by DNA methyltransferases to methylate the histones and regulate the gene expression. Particularly, these studies demonstrated that mice fed low-methionine food, compared to control mice, had high expression of miR-204 in the bone marrow; this miRNA regulates Osterix and RUNX2 in bone, inhibiting the amount and function of osteoblasts and by inducing bone fragility. Maternal bone mass decreases during lactation since skeletal calcium is released into breast milk. Although renal calcium excretion is reduced with increased tubular reabsorption and this is not sufficient to prevent bone loss. During lactation there is evidence of increased parathormone-related peptide (PTHrP) homologs with the N-terminal fragment of parathyroid hormone (PTH) produced by the mammary glands, which plays a key role in increasing blood calcium concentration and, in combination with low estradiol levels, leads to high rates of bone resorption. However, weaning triggers skeletal recovery that occurs very rapidly after the end of lactation [45].
Regarding the effects of the proteins, a study carried out on maternal nutrition has shown that a low-protein diet negatively regulates mother and child bone mass; however, there are no studies investigating the epigenetic effect of a high-protein diet.
Ioannis Kanakis et al. showed that there was a correlation between bone mineralization and the level of protein dietary intake during lactation in mice; the expression of RUNX2, as well as Alp and Col1a1, were all decreased mostly in mice with a low-protein intake diet compared to the control mice. This indicates a direct correlation resulting in decreased osteoblastic differentiation and activity, particularly in miR-26a, 34a and 125b expression. In deep, miR-125b normally regulates the osteogenic differentiation of human MSCs whilst miR-26a reverses the bone regeneration deficit of MSCs and miR-34a inhibits osteoclastogenesis. The main pathways concerned appear to be the Wnt and IL-6 signalling pathways [46]. Therefore, protein malnutrition increases bone loss, and slows down and delays bone recovery.
Fully understanding the mechanisms could lead to draft nutritional guidelines for improving bone health. However, the effects of dietary proteins on bone health must be considered according to age, health, the diet habits of the population and exercise practice [47]. Certainly, it is well known that a high protein intake increases urinary excretion of Calcium (Ca) and on average is estimated that at least 1 mg of Ca is excreted for each additional gram of protein consumed [48]. This relationship is mainly attributable to the metabolism of sulphur amino acids contained especially in animal proteins and some plant proteins, resulting in increased acidity buffered by organic calcium release from the skeleton. The effects of proteins on bones can also depend on the intake of foods rich in calcium and alkalis, such as fruits and vegetables. A low protein intake reduces insulin-like growth factor production, which in turn hinders calcium and phosphate metabolism, bone formation, and the promotion of satellite cell activation [49]. These effects probably depend on the amount and type of protein and influence bone health through epigenetic mechanisms [50].

This entry is adapted from the peer-reviewed paper 10.3390/genes14091667

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