Epigenetic Mechanisms in Bone Biology and Osteoporosis: Can They Drive Therapeutic Choices?

Abstract

Osteoporosis is a complex multifactorial disorder of the skeleton. Genetic factors are important in determining peak bone mass and structure, as well as the predisposition to bone deterioration and fragility fractures. Nonetheless, genetic factors alone are not sufficient to explain osteoporosis development and fragility fracture occurrence. Indeed, epigenetic factors, representing a link between individual genetic aspects and environmental influences, are also strongly suspected to be involved in bone biology and osteoporosis. Recently, alterations in epigenetic mechanisms and their activity have been associated with aging. Also, bone metabolism has been demonstrated to be under the control of epigenetic mechanisms. Runt-related transcription factor 2 (RUNX2), the master transcription factor of osteoblast differentiation, has been shown to be regulated by histone deacetylases and microRNAs (miRNAs). Some miRNAs were also proven to have key roles in the regulation of Wnt signalling in osteoblastogenesis, and to be important for the positive or negative regulation of both osteoblast and osteoclast differentiation. Exogenous and environmental stimuli, influencing the functionality of epigenetic mechanisms involved in the regulation of bone metabolism, may contribute to the development of osteoporosis and other bone disorders, in synergy with genetic determinants. The progressive understanding of roles of epigenetic mechanisms in normal bone metabolism and in multifactorial bone disorders will be very helpful for a better comprehension of disease pathogenesis and translation of this information into clinical practice. A deep understanding of these mechanisms could help in the future tailoring of proper individual treatments, according to precision medicine's principles.

Keywords: DNA methylation; fragility fracture; gene expression; histone modifications; microRNAs; precision medicine.

Figure 1

Schematic representation of the mechanism of action of epigenetic mechanisms. Histone acetylation positively regulates gene expression by inducing the opening of chromatin conformation and, thus, favouring the binding of transcription machinery. Histone methylation promotes the opening (panel A) or closing (panel B) of the chromatin conformation depending not only on the specific lysine residue modified, but also on its degree of methylation (Table 1). In this way, histone methylation can specifically induce or repress gene expression. MicroRNAs (miRNAs) suppress gene expression by selectively binding to the 3′ non coding region (3′UTR) of their mRNA targets through base-pairing. miRNAs can negatively regulate gene expression by two different post-transcriptional mechanisms: the cleavage of the mRNA target or the physical blocking of translation machinery. The choice of mechanism of action is determined only by the nucleotide complementarity between the miRNA and its mRNA target: the miRNA will cleave the target when it has sufficient complementarity to the miRNA itself, or it will repress translation, by physically blocking ribosome activity, if the mRNA does not have sufficient complementarity. In the first case, after the cleavage the miRNA remains intact and active and can proceed to the cleavage of other mRNA targets.

Figure 2

Schematic representation of the role of genetics and epigenetics in bone development and maintenance. Static genetic traits and dynamic epigenetic marks interact with inner and outer environmental stimuli to determine bone features at all ages. While genetics may modulate the expression of epigenetics marks, epigenetic markers can regulate the expression of many genes coding for key molecules driving skeletal modelling in growing bone and remodelling in adult bone. Thus, all processes from bone development to peak bone mass attainment and maintenance can be influenced by epigenetic signatures, implying the possibility of modulating epigenetics in order to prevent/treat bone deterioration.

Figure 3

Schematic representation of the role of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs induce histone acetylation by transferring an acetyl group from the acetyl coenzyme A to histone lysine side chains (mostly at histone 3 lysine 4 (H3K4Ac) or histone 3 lysine 9 (H3K9Ac)), inducing the opening of chromatin status and promoting gene transcription. Conversely, HDACs remove the acetyl groups from histones, inducing the closing of chromatin status and blocking gene transcription. Histone deacetylase inhibitors (HDIs) inhibit the catalytic activity of HDACs by directly binding to their catalytic sites.

Figure 4

Schematic representation of positive (↑) and negative (↓) miRNA regulators of osteoblast differentiation.

Figure 5

Schematic representation of positive (↑) and negative (↓) miRNA regulators of osteoclast differentiation.