Epigenetic regulation of bone remodeling by natural compounds

Abstract

Osteoporosis and osteopenia impact more than 54 million Americans, resulting in significant morbidity and mortality. Alterations in bone remodeling are the hallmarks for osteoporosis, and thus the development of novel treatments that will prevent or treat bone diseases would be clinically significant, and improve the quality of life for these patients. Bone remodeling involves the removal of old bone by osteoclasts and the formation of new bone by osteoblasts. This process is tightly coupled, and is essential for the maintenance of bone strength and integrity. Since the osteoclast is the only cell capable of bone resorption, the development of drugs to treat bone disorders has primarily focused on reducing osteoclast differentiation, maturation, and bone resorption mechanisms, and there are few treatments that actually increase bone formation. Evidence from observational, experimental, and clinical studies demonstrate a positive link between naturally occurring compounds and improved indices of bone health. While many natural extracts and compounds are reported to have beneficial effects on bone, only resveratrol, sulforaphane, specific phenolic acids and anthocyanins, have been shown to both increase bone formation and reduce resorption through their effects on the bone epigenome. Each of these compounds alters specific aspects of the bone epigenome to improve osteoblast differentiation, reduce osteoblast apoptosis, improve bone mineralization, and reduce osteoclast differentiation and function. This review focuses on these specific natural compounds and their epigenetic regulation of bone remodeling.

Keywords: Anthocyanins; DNA methylation; Ferulic acid; Non-coding RNA; Osteoblast; Osteoclast; Resveratrol; Sulforaphane; Syringic acid.

Figure 1.

Heritable, endogenous and exogenous factors affecting bone modeling/remodeling in vertebrates.

Figure 2.

A simplified schematic diagram depicting an overview of histone-modifying enzymes, focusing primarily on histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyl transferases (HTMs), and histone demethylases (HDMs) and their enzymatic effects on chromatin structure. Sirtuins are a subclass of HDACs (class III) and are a NAD+-dependent deacetylases.

Figure 3.

A schematic diagram of osteoblast and osteoclast differentiation from mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), outlining some of the miRNAs involved in these processes and their effects on important transcription factors and genes involved. The arrows represent activation or active processes, the dashed lines represent indirect inactivation and the solid black lines represent direct inactivation.

Figure 4.

Resveratrol impacts bone remodeling by increasing SIRT1 and ATP production in osteoblasts. Treatment of osteoblast with resveratrol, activates mitochondrial complex I in the electron transport chain, increasing production of NAD+ and ATP formation, leading to an alteration in the NAD+/NADH ratio and thereby activating SIRT1 and increasing osteoblast differentiation and function.

Figure 5.

Schematic diagram of the effects of resveratrol and anthocyanins/anthocyanidins (delphinidin and delphinidin-3-glucoside) on SIRT1 activation and increased osteoblastogenesis. These compounds also reduced osteoclastogenesis by reducing the expression of RANKL, NF-κβ and cathepsin K.

Figure 6.

Sulforaphane increases bone formation and reduces bone resorption by promoting osteoblast differentiation via epigenetic alterations in DNA methylation and alterations of gene expression. Sulforaphane also induced pre-osteoclast apoptosis.

Figure 7.

A flow chart of the effects of ferulic acid on mesenchymal stem cells (MSCs) and their differentiation into osteoblasts. Treatment of MSCs with ferulic acid activated HIF1α and down-regulated miR-340-5p expression. This increased β-catenin Wnt signaling resulting in an increased expression of Runx2 and osterix/sp7, two critical factors in osteoblast differentiation. These events lead to increased expression of alkaline phosphatase (ALP) in differentiated osteoblast.

Figure 8.

A flow chart of the effects of syringic acid on mesenchymal stem cells (MSCs) and their differentiation into osteoblasts. Treatment of MSCs with syringic acid upregulates miR-21 expression, and reduces Smad7 expression resulting in an increased expression of Runx2, a critical factor in osteoblast differentiation. These events lead to increased expression of the genes ALP, Col-1, and OC in differentiated osteoblast. ALP = alkaline phosphatase; Col-1 = type 1 collagen 1; OC = osteocalcin

Figure 9.

Anthocyanins from fruit extracts increase osteoblastogenesis and reduce osteoblast apoptosis in hFOB human osteoblasts and transgenic medaka by epigenetic regulation of SIRT1/3 and PGC-1α. In osterix/sp7:mCherry transgenic medaka treatment increased osteoblast differentiation and proliferation as well as the expression of osterix/sp7 and Runx2.