Epigenetic pathways regulating bone homeostasis: potential targeting for intervention of skeletal disorders

Abstract

Epigenetic regulation utilizes different mechanisms to convey heritable traits to progeny cells that are independent of DNA sequence, including DNA silencing, post-translational modifications of histone proteins, and the post-transcriptional modulation of RNA transcript levels by non-coding RNAs. Although long non-coding RNAs have recently emerged as important regulators of gene imprinting, their functions during osteogenesis are as yet unexplored. In contrast, microRNAs (miRNAs) are well characterized for their control of osteogenic and osteoclastic pathways; thus, further defining how gene regulatory networks essential for skeleton functions are coordinated and finely tuned through the activities of miRNAs. Roles of miRNAs are constantly expanding as new studies uncover associations with skeletal disorders. The distinct functions of epigenetic regulators and evidence for integrating their activities to control normal bone gene expression and bone disease will be presented. In addition, potential for using "signature miRNAs" to identify, manage, and therapeutically treat osteosarcoma will be discussed in this review.

Fig. 1

Epigenetic mechanisms regulating biological systems. The four types of epigenetic control of gene expression (black boxes) are illustrated by their effect of DNA structure (schematic) and their functional activity. DNA methylation is the major contributor to heritable traits. Mitotic bookmarking contributes to cell phenotype stability during cell division. Histone modifications on amino acids in tails of histone proteins (e.g., acetylation, methylation, phosphorylation) alter DNA structure to facilitate accessibility of transcription factor binding. RNA machinery involves several classes of small and long non-coding RNAs; the miRNAs are extensively discussed in this review, as they have greatly impacted on bone biology and represent promise of therapeutic applications for bone diseases