Genetics and Epigenetics of Bone Remodeling and Metabolic Bone Diseases

Abstract

Bone metabolism consists of a balance between bone formation and bone resorption, which is mediated by osteoblast and osteoclast activity, respectively. In order to ensure bone plasticity, the bone remodeling process needs to function properly. Mesenchymal stem cells differentiate into the osteoblast lineage by activating different signaling pathways, including transforming growth factor β (TGF-β)/bone morphogenic protein (BMP) and the Wingless/Int-1 (Wnt)/β-catenin pathways. Recent data indicate that bone remodeling processes are also epigenetically regulated by DNA methylation, histone post-translational modifications, and non-coding RNA expressions, such as micro-RNAs, long non-coding RNAs, and circular RNAs. Mutations and dysfunctions in pathways regulating the osteoblast differentiation might influence the bone remodeling process, ultimately leading to a large variety of metabolic bone diseases. In this review, we aim to summarize and describe the genetics and epigenetics of the bone remodeling process. Moreover, the current findings behind the genetics of metabolic bone diseases are also reported.

Keywords: DNA methylation; bone disease; bone formation; bone morphogenic protein; bone remodeling; histone post-translational modifications; long non-coding RNA; metabolic bone disease; microRNA; non-coding RNA; osteogenesis.

Figure 1

Schematic illustration of the Wingless/Int-1 (Wnt) signaling pathway. The Wnt signaling pathway and its components reported to be mutated in metabolic bone disease are reported. Activation of the canonical Wnt pathway leads to an increase in bone mass. Wnt ligands interact with co-receptor LRP5/6 and frizzled (FZD) to activate the Wnt signaling pathway. The inhibition of Wnt signaling is mediated by extracellular factors, such as sclerostin (SOST) and Dickkopf-related protein 1 (DKK-1) and leads to bone mass decrease. DKK-1 binds to the LRP5/6 co-receptor, thereby preventing activation by Wnt ligands. Inhibitory transmembrane protein LRP4, which is a SOST-interacting protein, is recruited and the Kremen proteins, which are high-affinity DKK-1 receptors, cooperate with DKK-1 to decrease Wnt signaling. In addition, secreted frizzled-related protein (SFRP) inhibits the canonical Wnt pathway by sequestering Wnt ligands. Mutations in Wnt signaling components result in pathway activation/inhibition. For example, loss-of-function mutations affecting SOST and LRP4 lead to Wnt pathway activation causing bone tissue sclerosteosis, as well as loss-of-function mutations of LRP5 and the WNT1 ligand result in Wnt signaling pathway inhibition leading to osteoporosis disorders.