The Roles of Epigenetics Regulation in Bone Metabolism and Osteoporosis

Abstract

Osteoporosis is a metabolic disease characterized by decreased bone mineral density and the destruction of bone microstructure, which can lead to increased bone fragility and risk of fracture. In recent years, with the deepening of the research on the pathological mechanism of osteoporosis, the research on epigenetics has made significant progress. Epigenetics refers to changes in gene expression levels that are not caused by changes in gene sequences, mainly including DNA methylation, histone modification, and non-coding RNAs (lncRNA, microRNA, and circRNA). Epigenetics play mainly a post-transcriptional regulatory role and have important functions in the biological signal regulatory network. Studies have shown that epigenetic mechanisms are closely related to osteogenic differentiation, osteogenesis, bone remodeling and other bone metabolism-related processes. Abnormal epigenetic regulation can lead to a series of bone metabolism-related diseases, such as osteoporosis. Considering the important role of epigenetic mechanisms in the regulation of bone metabolism, we mainly review the research progress on epigenetic mechanisms (DNA methylation, histone modification, and non-coding RNAs) in the osteogenic differentiation and the pathogenesis of osteoporosis to provide a new direction for the treatment of bone metabolism-related diseases.

Keywords: DNA methylation; epigenetics; histone modification; non-coding RNA; osteoporosis.

FIGURE 1

The schematic diagram of bone remodeling process (Chen et al., 2018; Foger-Samwald et al., 2020; Gkastaris et al., 2020; Zou et al., 2020). Bone remodeling process is initiated by osteoclasts that solubilize bone mineral and degrade the matrix (resorption phase). Osteoclasts originate from hematopoietic stem cells which differentiate first into pre-osteoclast cells which fuse to form multinucleated cells (activated osteoclasts). Monocytes/macrophages remove debris (reversal phase), followed by a bone formation phase performed by osteoblasts, producing osteoid matrix which will mineralize. Growth factors are released from the bone matrix during resorption, which increase the pre-osteoblast population in order to replace damaged bone surfaces.

FIGURE 2

Molecular mechanism of DNA methylation (Yang and Duan, 2016; Letarouilly et al., 2019; Ahmed et al., 2020; Wang et al., 2020; Xu et al., 2020). DNA methylation modification is mainly controlled by DNMT proteins. S-adenosylmethionine is used as the methyl donor to methylate the cytosine on CpG islands. Normally, the CpG island of a gene is in an unmethylated state. Methylation of the cytosines in the CpG island can inhibit the expression of this gene.

FIGURE 3

Regulatory effect of methylation levels of bone metabolism-related genes on bone formation (Kitazawa and Kitazawa, 2007; Delgado-Calle et al., 2012; Fu et al., 2013; Cao et al., 2019; Kalkan and Becer, 2019; Licini et al., 2019; Raje and Ashma, 2019; Chen D. et al., 2020; Kim et al., 2020). RUNX2 and OSX are specific transcription factors, which synergistically regulate the expression of bone-specific genes, including those encoding ALP, type I collagen and OCN. BMP2 is a key bone growth factor that can stimulate MSCs to differentiate into osteoblasts by inducing the expression of genes such as those encoding RUNX2, OSX, and OCN. The hypermethylation of the BMP2 promoter region in osteoblasts leads to downregulation of bone formation markers. SOST, a glycoprotein mainly secreted by osteoblasts, can inhibit osteoblast differentiation by inhibiting Wnt signal transduction and negatively regulates bone formation. The hypermethylation of SOST can inhibit SOST gene translation and promote the osteoclast differentiation. DNA methylation can regulate the transcription and expression of Wnt/β-catenin signalling pathway molecules, so as to regulate the differentiation and function of osteoblasts. OPG/RANK/RANKL is the main regulator of the balance between osteoblasts and osteoclasts. The methylation of these gene promoter regions can regulate the expression of corresponding genes, thus affecting the differentiation and function of osteoblast/osteoclast, and finally affecting the dynamic balance between bone formation and bone absorption in the process of bone remodeling (Niu et al., 2020).

FIGURE 4

Illustration of SIRT1 signaling pathway in bone remodeling (Cohen-Kfir et al., 2011; Shakibaei et al., 2011; Edwards et al., 2013; Feng et al., 2014; Iyer et al., 2014; Kim et al., 2015; Liu J. et al., 2016). SIRT1 participates in intracellular energy metabolism through AMPK signaling pathway, and regulates bone metabolism in an AMPK-dependent manner. SIRT1 can promote the differentiation of MSCs into osteoblasts by directly deacetylating SOX2. SIRT1 can deacetylate β-catenin and promote β-catenin to accumulate in the nucleus, thus further activating Wnt pathway to promote Osteogenesis differentiation. SIRT1 can activate the transcription factor RUNX2 and promote the differentiation of MSCs into osteoblasts. Activation of SIRT1 can significantly increase the expression level of BMP-2 and BMP-7 to promote bone repair. SIRT1 inhibits NF-κB degradation, downregulates NF-κB signaling and inhibits bone resorption. Activation of SIRT1 can significantly inhibit the activity of MAPK signaling pathway by inhibiting the expression of prostaglandin, promote the expression of OPG and inhibit osteoclast generation and bone resorption (Yang and Tang, 2019).

FIGURE 5

Schematic drawing of functional lncRNAs implicated in osteoporosis (Keniry et al., 2012; Zhu and Xu, 2013; Chan et al., 2014; Che et al., 2015; Tong et al., 2015; Xiao et al., 2015; Xu et al., 2015; Huang et al., 2016; Liang et al., 2016; Zhu et al., 2016; Chen et al., 2017; Wang et al., 2017; Wei et al., 2017; Weng et al., 2017; Xia et al., 2017; Zhang et al., 2017; Feng X. et al., 2018; Feng L. et al., 2018; Li H. et al., 2018; Sun X. et al., 2018; Liu et al., 2019; Yang et al., 2019a; Zhu E. et al., 2019; Zhu J. et al., 2019).

FIGURE 6

LncRNA H19 regulates the gene pathway of osteogenic differentiation through the lncRNA-miRNA-mRNA network (Keniry et al., 2012; Chan et al., 2014; Huang et al., 2016; Liang et al., 2016; Liao et al., 2020). H19 can up-regulate the expression of miR-675, further inhibit the phosphorylation of TGF-1 and Smad3, and downregulate the expression of Histone deacetylase 4/5 (HDAC4/5), and promote the expression of genes related to osteogenic differentiation; H19 can inhibit the expression of miRNAs (miR-141 and miR-22), promote Wnt/β-catenin signal transduction pathway, and promote osteogenic differentiation; H19 can regulate the expression of ligands such as Dll1, Dll3, Dll4, Jag1, and Jag2 in Notch signaling pathway by regulating the expression of miRNA (miR-107, miR-27b, miR-106b, miR-125a, and miR-17) to further promote the induction of the osteogenic differentiation by BMP9 (Zhang et al., 2018).

FIGURE 7

Schematic drawing of miRNAs implicated in osteoblast differentiation (Li et al., 2009, 2012, 2015; Hu et al., 2011; Wu et al., 2012; Zhang et al., 2012; Grunhagen and Ott, 2013; Liu et al., 2013, 2020; Wang et al., 2013; Kato et al., 2014; Kureel et al., 2014; Li E. et al., 2014; Qi and Zhang, 2014; Sun et al., 2014, 2016; Yang et al., 2014, 2017; Xiao et al., 2016; Zheng et al., 2017; Xie and Cao, 2019; Zhang L. et al., 2019; Krzeszinski et al., 2020; Yan et al., 2020).