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The effect of epigenetic mechanisms on gene expression influences many processes of the human body. Mechanisms such as histone acetylation and deacetylation can affect normal rates of bone resorption and bone formation in bone remodeling, which in turn may be factors in causing bone-related diseases such as osteoporosis.

Background
Bone resorption is mediated by osteoclasts and bone formation is mediated by osteoblasts. Bone resorption and bone formation together interact through gene expression to maintain mineral homeostasis. These processes are influenced by environmental factors that can lead to epigenetic changes in gene expression.

Osteoblast Differentiation
Osteoblasts are derived from mesenchymal stem cells and are essential for bone formation. The differentiation of mesenchymal stem cells to osteoblast is regulated by the Cbfa1/RUNX2 transcription factor. The presence of the RUNX2 transcription factor is necessary for this process, and its absence results in the lack of bone formation. RUNX2, in turn, is regulated by BMP, Wnt, and Notch.

Osteoclast Differentiation
Osteoclast differentiation is regulated through a different set of signaling pathways and transcription factors. One important system that determines the differentiation of osteoblast precursors (OCPs) is the RANKL/RANK/OPG system. RANKL expression by osteoblastic stromal cells and RANK receptor expression by OCPs is essential for OCPs to differentiation into osteoclasts. Activation of transcription factors such as PU.1, MITF, and NFκB, and NFATC1 also mediate OCP differentiation into osteoclasts.

Osteoprotegrin (OPG) is part of the TNF superfamily and acts as a decoy receptor for RANKL, preventing RANKL binding to RANK and thus reducing bone resorption. OPG expression is regulated by the Wnt/β-catenin and Jagged1/Notch1 signaling pathways that also play a role in osteoblast differentiation. Osteoprotegrin is important for maintaining normal bone mass. Absence of OPG results in increased bone resorption and early onset osteoporosis, demonstrating the close relationship between bone resorption and formation in bone remodeling.

Epigenetic Effects
Given the importance of signaling pathway in regulating bone remodeling, epigenetic mechanisms, such as histone deacetylation, DNA methylation, and miRNA-mediated post-transcriptional regulation, likely play a large role in influencing the rate of bone resorption and formation. Epigenetic influence on bone remodeling will likely provide more insight into causes of and possible preventative measures that can be taken against bone-related disease.

Epigenetic Regulation of Osteoblast Differentiation
Histone deacetylase inhibitors (HDIs) are shown to have an impact on osteoblast differentiation. Histone acetyltransferases (HATs) that are recruited onto promoter regions are able to promote transcriptional activity. They are negated by histone deacetylases (HDACs), which conversely removes acetyl groups, promote chromatin condensation, and thus reduce or repress transcriptional activity. Histone deacetylase inhibitors, in turn, block the activity of Class I and II HDACs, promoting histone hyperacetylation and gene expression. Osteoblast precursor cells treated with HDI showed greater osteoblast differentiation and increased expression levels of the RUNX2 transcription factor and increased alkaline phosphatase activity, which are a sign of osteoblast activity and bone formation.



Studies of the osteocalcin gene also reveals a greater connection between histone acetylation and osteoblast differentiation. Enhancement of the OC gene results in histone modifications that cause chromatin remodeling that allows for Cbfa1/Runx2 transcription factors to bind to the OC gene promoter. ChIP assays reveal that acetylated histones H3 and H4 associate with the promoter of the OC gene only when it is transcriptionally active in mature osteoblasts. The OC gene was found to contain low levels of acetylated histones H3 and H4 during osteoblast proliferation, during which the gene is inactive.

Epigenetic Regulation of Osteoclast Differentiation
Inhibition of Class I or Class II HDACs is able to suppress osteoclast differentiation and undergo increased cell apoptosis. Transcription factors necessary for osteoclast differentiation, such as NFκB and MAPK, also show reduced activation. Histone deacetylase inhibitors were able to inhibit growth of osteclast precursor cells and multinucleated osteoclasts. HDIs are able to promote osteoblast differentiation and bone formation while reducing osteoclast differentiation and thus bone resorption. While research into epigenetic effects on osteoclast differentiation and proliferation is far less studied than the epigenetic effects on osteoblast differentiation, there is clear evidence that epigenetic mechansims such as histone acetylation, histone deacetylases, histone deacetylase inhibitors have a significant impact on maintaining bone mass homeostasis.