Many crucial epigenetic changes occur during early skeletal development and throughout life due to aging, disease and are heavily influenced by an individual’s lifestyle. Epigenetics is the study of heritable changes in gene expression as the result of changes in the environment without any mutation in the underlying DNA sequence. The epigenetic profiles of cells are dynamic and mediated by different mechanisms, including histone modifications, non-coding RNA-associated gene silencing and DNA methylation. Given the underlining role of dysfunctional mesenchymal tissues in common age-related skeletal diseases such as osteoporosis and osteoarthritis, investigations into skeletal stem cells or mesenchymal stem cells (MSC) and their functional deregulation during aging has been of great interest and how this is mediated by an evolving epigenetic landscape. The present review describes the recent findings in epigenetic changes of MSCs that effect growth and cell fate determination in the context of aging, diet, exercise and bone-related diseases.

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Impact of Environmental and Epigenetic Changes on Mesenchymal Stem Cells during Aging

Bone formation and homeostasis are controlled by environmental factors and endocrine regulatory cues that initiate intracellular signaling pathways capable of modulating gene expression in the nucleus. Bone-related gene expression is controlled by nucleosome-based chromatin architecture that limits the accessibility of lineage-specific gene regulatory DNA sequences and sequence-specific transcription factors. From a developmental perspective, bone-specific gene expression must be suppressed during the early stages of embryogenesis to prevent the premature mineralization of skeletal elements during fetal growth in utero. Hence, bone formation is initially inhibited by gene suppressive epigenetic regulators, while other epigenetic regulators actively support osteoblast differentiation. Prominent epigenetic regulators that stimulate or attenuate osteogenesis include lysine methyl transferases (e.g., EZH2, SMYD2, SUV420H2), lysine deacetylases (e.g., HDAC1, HDAC3, HDAC4, HDAC7, SIRT1, SIRT3), arginine methyl transferases (e.g., PRMT1, PRMT4/CARM1, PRMT5), dioxygenases (e.g., TET2), bromodomain proteins (e.g., BRD2, BRD4) and chromodomain proteins (e.g., CBX1, CBX2, CBX5). This narrative review provides a broad overview of the covalent modifications of DNA and histone proteins that involve hundreds of enzymes that add, read, or delete these epigenetic modifications that are relevant for self-renewal and differentiation of mesenchymal stem cells, skeletal stem cells and osteoblasts during osteogenesis. 

Epigenetic regulators controlling osteogenic lineage commitment and bone formation.

Epigenetics and the role of nutraceuticals in health and disease

Bone metabolism plays a crucial role in maintaining normal bone tissue homeostasis and function. Imbalances between bone formation and resorption can lead to osteoporosis, osteoarthritis, and other bone diseases. The dynamic and complex process of bone remodeling is driven by various factors, including epigenetics. Histone modification, one of the most important and well-studied components of epigenetic regulation, has emerged as a promising area of research in bone metabolism. Different histone proteins and modification sites exert diverse effects on osteogenesis and osteoclastogenesis. In this review, we summarize recent progress in understanding histone modifications in bone metabolism, including specific modification sites and potential regulatory enzymes. Comprehensive knowledge of histone modifications in bone metabolism could reveal new therapeutic targets and treatment strategies for bone diseases. 

Unlocking the potential of histone modification in regulating bone metabolism

Intrauterine growth restriction (IUGR) affects a large proportion of infants, particularly in underdeveloped countries. Among the main causes of IUGR, maternal endocrine-metabolic dysfunction is highlighted, either due to its high incidence or due to the severity of the immediate and mediated changes that these dysfunctions cause in the fetus and the mother. Although the effects of endocrine and metabolic disorders have been widely researched, there are still no reviews that bring together and summarize the effects of these conditions on bone development in cases of IUGR. Therefore, the present literature review was conducted with the aim of discussing bone changes observed in fetuses with IUGR caused by maternal endocrine-metabolic dysfunction. The main endocrine dysfunctions that occur with IUGR include maternal hyperthyroidism, hypothyroidism, and hypoparathyroidism. Diabetes mellitus, hypertensive disorders, and obesity are the most important maternal metabolic dysfunctions that compromise fetal growth. The bone changes reported in the fetus are, for the most part, due to damage to cell proliferation and differentiation, as well as failures in the synthesis and mineralization of the extracellular matrix, which results in shortening and fragility of the bones. Some maternal dysfunctions, such as hyperthyroidism, have been widely studied, whereas conditions such as hypoparathyroidism and gestational hypertensive disorders require further study regarding the mechanisms underlying the development of bone changes. Similarly, there is a gap in the literature regarding changes related to intramembranous ossification, as most published articles only describe changes in endochondral bone formation associated with IUGR. Furthermore, there is a need for more research aimed at elucidating the late postnatal changes that occur in the skeletons of individuals affected by IUGR and their possible relationships with adult diseases, such as osteoarthritis and osteoporosis. 

Bone development in fetuses with intrauterine growth restriction caused by maternal endocrine-metabolic dysfunctions

ABSTRACT Studies from both humans and animal models indicated that maternal chronic poor-quality diet, especially a high fat diet (HFD), is significantly associated with reduced bone density and childhood fractures in offspring. When previously studied in a rat model, our data suggested that maternal HFD changes epigenetic marks such as DNA methylation and histone modifications to control osteoblast metabolism. In mouse embryonic and postnatal offspring bone samples, a ChIP-sequencing (ChIP-Seq)-based genome-wide method was used to locate the repressive histone mark H3K27me3 (mediated via the polycomb histone methyltransferase, Ezh2) and expressive histone mark H3K27ac (p300/CBP mediated) throughout the genome. Using isolated mouse embryonic cells from foetal calvaria (osteoblast-like cells), H3K27me3 ChIP-Seq showed that 147 gene bodies and 26 gene promoters in HFD embryotic samples had a greater than twofold increase in H3K27me peaks compared to controls. Among the HFD samples, Pthlh and Col2a1 that are important genes playing roles during chondro- and osteogenesis had significantly enriched levels of H3K27me3. Their decreased mRNA expression was confirmed by real-time PCR and standard ChIP analysis, indicating a strong association with Ezh2 mediated H3K27me3 epigenetic changes. Using embryonic calvaria osteoblastic cells and offspring bone samples, H3K27ac ChIP-Seq analysis showed that osteoblast inhibitor genes Tnfaip3 and Twist1 had significantly enriched peaks of H3K27ac in HFD samples compared to controls. Their increased gene expression and association with H3K27ac were also confirmed by real-time PCR and standard ChIP analysis. These findings indicate that chronic maternal HFD changes histone trimethylation and acetylation epigenetic marks to regulate expression of genes controlling osteoblastogenesis.

Maternal high-fat diet modifies epigenetic marks H3K27me3 and H3K27ac in bone to regulate offspring osteoblastogenesis in mice

Phenolic acids, such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA), can be produced from microbiome digestion of polyphenols. Previously it was found that HA and 3-3-PPA facilitate bone formation and suppress bone resorption. However, the mechanism of action by which HA and 3-3-PPA protect bone from degeneration is currently unknown. In this report, we present that HA and 3-3-PPA suppression of bone resorption is able to ameliorate bone loss in an ovariectomy (OVX) osteopenic mouse model though not to the extent of Zoledronic acid (ZA). HA and 3-3-PPA treatments were shown to significantly decrease bone marrow adipocyte-like cell formation and inhibited gene expression of key adipogenesis regulator peroxisome proliferator activated receptor gamma (PPARγ) and lipoprotein lipase (Lpl) in bone from OVX mice. In addition, ChIP experiments showed that the association between PPARγ and Lpl promoter region in pre-adipocyte-like cells was significantly suppressed following HA or 3-3-PPA treatment. Contrasting HA and 3-3-PPA, ZA significantly increased TRAP activity in the area close to growth plate and significantly suppressed bone cell proliferation. These data suggest that phenolics acids such as HA or 3-3-PPA may prevent bone degeneration after OVX through suppression of inflammatory milieu in the bone. 

Phenolic acids prevent sex-steroid deficiency-induced bone loss and bone marrow adipogenesis in mice.

Sex-dependent effect of GPR109A gene deletion in myeloid cells on bone development in mice

Osteoclasts derived from hematopoietic stem cells control bone resorption. Identifying novel molecules that can epigenetically regulate osteoclastogenesis is important for developing novel treatments for osteoporosis and other disorders associated with bone deterioration and promoting healthy bone formation. The polycomb group (PcG) protein enhancer of zeste homolog 2 (Ezh2), a histone lysine methyltransferase, is associated with epigenetic regulation of numerous cellular processes, but its involvement in bone cell development and homeostasis is not yet clear. Here, LysM‐Cre mice were crossed with Ezh2flox/flox mice to delete Ezh2 in myeloid cell lineage mature macrophages. Conditional knockout of Ezh2 (CKO) in myeloid cell line resulted in significant increases in postnatal bone growth in the first 6 months of life for both male and female mice. For female mice, optimal bone mass was seen for mice with Ezh2 deleted in both chromosomes in a pair (f/f Cre+; CKO). For male mice, optimal bone mass was found after deletion of Ezh2 from just one chromosome (f/− Cre+) with no difference in bone phenotype between f/− Cre+ and CKO male mice. In addition to the gender‐specific difference in bone phenotype, Ezh2 CKO mice had significantly less macrophages (CD11b+) present in the bone marrow compared with control mice as well as significantly more mature osteoblasts and bone formation biomarkers present (P1NP, osteocalcin). Inflammatory array for protein lysed from bone tissue revealed deletion of Ezh2 decreased inflammatory milieu in both male and female mice compared with controls. Unexpectedly, myeloid cell deletion of Ezh2 also increased the number of mature osteoblast present in the bone. Deletion of Ezh2 also led to an increase in gene expression of osteoclast‐suppressive genes IRF8, MafB, and Arg1 due to a decrease in the presence of the suppressive H3K27me3 epigenetic mark. These findings suggest that manipulation of Ezh2 expression may be a viable strategy to combat bone resorptive disorders such as osteoporosis or arthritis.

Decreased bone resorption in Ezh2 myeloid cell conditional knockout mouse model

Abstract In multiple myeloma (MM), increased osteoclast differentiation leads to the formation of osteolytic lesions in most MM patients. Bisphosphonates, such as zoledronic acid (ZA), are used to ameliorate bone resorption, but due to risk of serious side effects as well as the lack of repair of existing lesions, novel anti-bone resorption agents are required. Previously, the absence of osteolytic lesions in MM was strongly associated with elevated levels of cystatin M/E (CST6), a cysteine protease inhibitor, secreted by MM cells. In this study, both MM- and ovariectomy (OVX)-induced osteoporotic mouse models were used to compare the effects of recombinant mouse CST6 (rmCst6) and ZA on preventing bone loss. µCT showed that rmCst6 and ZA had similar effects on improving percent bone volume, and inhibited differentiation of non-adherent bone marrow cells into mature osteoclasts. Single-cell RNA sequencing showed that rmCst6 and not ZA treatment reduced bone marrow macrophage percentage in the MM mouse model compared to controls. Protein and mRNA arrays showed that both rmCst6 and ZA significantly inhibit OVX-induced expression of inflammatory cytokines. For OVX mice, ERα protein expression in bone was brought to sham surgery level by only rmCst6 treatments. rmCst6 significantly increased mRNA and protein levels of ERα and significantly increased total intracellular estrogen concentrations for ex vivo osteoclast precursor cell cultures. Based on these results, we conclude that CST6 improves MM or OVX bone loss models by increasing the expression of estrogen receptors as well as the intracellular estrogen concentration in osteoclast precursors, inhibiting their maturation.

Cystatin M/E ameliorates bone resorption through increasing osteoclastic cell estrogen influx

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