Abstract
Epigenetic mechanisms including posttranslational histone modifications and DNA methylation are emerging as important determinants of bone homeostasis. With our case-control study we aimed to identify which chromatin-modifying enzymes could be involved in the pathology of postmenopausal osteoporosis and osteoarthritis while co-regulated by estrogens, oxidative stress and hypoxia. Gene expression of HAT1, KAT5, HDAC6, MBD1 and DNMT3A affected by oxidative stress and hypoxia in an in vitro qPCR screening step performed on an osteoblast cell line was analysed in trabecular bone tissue samples from 96 patients. Their expression was significantly reduced in patients with postmenopausal osteoporosis and osteoarthritis as compared to autopsy controls and significantly correlated with bone mineral density and several bone histomorphometry-derived parameters of bone quality and quantity as well as indicators of oxidative stress, RANK/RANKL/OPG system and angiogenesis. Furthermore, oxidative stress increased DNA methylation levels at the RANKL and OPG promoters while decreasing histone acetylation levels at these two genes. Our study is the first to show that higher expression of HAT1, HDAC6 and MBD1 is associated with superior quantity as well as quality of the bone tissue having a more favourable trabecular structure.
Highlights
Epigenetic mechanisms represent an important ubiquitous group of gene expression regulators associated with normal and aberrant bone remodelling and homeostasis[1]
I.e. HAT1, HDAC6 and methyl-CpG binding domain protein 1 (MBD1), exhibited the biggest variation between our three patient groups. This together with their significant correlation with a number of measured bone tissue phenotype parameters indicates that higher expression of HAT1, HDAC6 and MBD1 is associated with superior
Even though oxidative stress has been primarily associated with bone loss in postmenopausal osteoporosis (PMO) patients, our results revealed the highest expression of aldehyde oxidase 1 (AOX1) in OA bone tissue[18]
Summary
Epigenetic mechanisms represent an important ubiquitous group of gene expression regulators associated with normal and aberrant bone remodelling and homeostasis[1]. It is mediated by DNA methyltransferases (DNMTs) and facilitates binding of various DNA methyl-binding proteins to the DNA molecule[2] Any of these epigenetic mechanisms could be modified by different environmental factors, like oxidative stress, hypoxia and estrogens which are some of the known factors influencing bone remodelling in complex in vivo conditions. 17β-estradiol reduces bone remodelling and reciprocally affects differentiation and apoptosis of osteoblasts and osteoclasts, thereby reducing bone resorption and increasing bone formation These effects are at least in part mediated through WNT/β-catenin signalling pathway and RANK/RANKL/OPG system. The most exciting genes from the in vitro study were measured in human bone tissue samples of PMO and OA patients and controls Their expression was correlated with clinically relevant phenotype data like bone mineral density (BMD), micro computed tomography (μCT) and bone histomorphometric (BHM) measurements as well as the indicators of oxidative stress, RANK/RANKL/OPG system and angiogenesis. The impact of H2O2 on the DNA methylation and histone acetylation state of HOS cells was evaluated for the highly relevant receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) genes
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