Epigenetic regulation of bone cells

Abstract

Bone is a major organ in the skeletal system that supports and protects muscles and other organs, facilitates movement and hematopoiesis, and forms a reservoir of minerals including calcium. The cells in the bone, such as osteoblasts, osteoclasts, and osteocytes, orchestrate sequential and balanced regulatory mechanisms to maintain bone and are capable of differentiating in bones. Bone development and remodeling require a precise regulation of gene expressions in bone cells, a process governed by epigenetic mechanisms such as histone modification, DNA methylation, and chromatin structure. Importantly, lineage-specific transcription factors can determine the epigenetic regulation of bone cells. Emerging data suggest that perturbation of epigenetic programs can affect the function and activity of bone cells and contributes to pathogenesis of bone diseases, including osteoporosis. Thus, understanding epigenetic regulations in bone cells would be important for early diagnosis and future therapeutic approaches.

Keywords: DNA methylation; epigenetic regulation; histone modification; osteoblasts; osteoclasts.

Figure 1. The process of bone remodeling and epigenetic factors

Bone is maintained by bone remodeling which is a continuous cycle of bone resorption and bone formation. Bone remodeling is a coupled and balanced process and takes place in basic multicellular units. In a resting stage, the non-remodeling bone surface is covered by bone lining cells. Osteocytes sense bone damages and recruit osteoclast precursor cells (OCPs), which further differentiate into mature osteoclasts. Osteoclasts resorb a damaged or old bone matrix and subsequently osteoblasts are recruited into resorbed sites and form new bone. Osteoclasts are differentiated from hematopoietic stem cells (HSCs). M-CSF and RANKL are key drivers of osteoclastogenesis. M-CSF enables HSCs to differentiate into OCPs which express RANK, a receptor for RANKL. RANKL further promotes OCPs into mature osteoclasts. Mesenchymal stem cells (MSCs) differentiate into osteoblasts and classical coupling factors, which are released from resorbed bone matrix or produced by osteoclasts, promote osteogenic differentiation through the osteoblast lineage. Key transcription factors (orange boxes), epigenetic enzymes that participate in DNA methylation (blue boxes), and histone deacetylases (yellow boxes) are indicated and described in the text.

Figure 2

A. The core proteins of nucleosomes are two copies of H2A, H2B, H3, and H4 and 146 base pairs of DNA wraps around these core histone octamer. Core histones are highly conserved and have amino-terminal tails which are subject to various post-translational modifications. Histone modifications, such as methylation and acetylation, play an important role in gene expression and active promoter regions are distinguished by specific histone modifications including H3K4me3 and H3K27Ac. Nucleosomes are depleted in highly active regions, called “open chromatin”. Transcription factors and lineage determining factors such as NFAT and RUNX2 bind to a specific binding motif in promoters or enhancers. Ac, acetylation; Me, methylation. B. Histone modifications of functional elements including promoters, enhancers, and insulators. Insulator is a genetic boundary element that blocks the interaction between enhancers and promoters and is defined by CCCTC-binding factor (CTCF) binding although CTCF has dual effects on enhancers; either blocking or activating. Active promoters are enriched for H3K4me3 and H3/H4 acetylation. H3K9 me2/3 and H3K27me3 are associated with repressed promoter regions. Active enhancers are marked by H3Kme1 and H3K27Ac.