br Epigenetic regulation of OA

Epigenetic regulation of OA pathogenesis Although epigenome of each cell is unique but can undergo temporal and spatial changes in response to environmental stimuli such as diet, exercise, smoking and disease status. Aberrant epigenetic modifications due to environmental factors are associated with a number of pathological conditions and include DNA methylation, non-coding RNAs (ncRNAs) expression and histone modifications that regulate the gene expression at transcriptional and/or post-transcriptional levels (Fig. 1). Here, we will briefly highlight the first two epigenetic mechanisms namely DNA methylation and ncRNA mediated regulation of gene expression in OA and will focus on HDACs mediated regulation of OA pathogenesis and explore the potential of HDACs inhibitors (HDACi) for the management of OA.
Conflict of interest disclosure
Introduction Chronic kidney disease (CKD) is an increasingly common public health issue that can result in gradual and irreversible renal tissue injury, dysfunction, and nephron loss [1].Renal interstitial fibrosis is a characteristic feature of all forms of CKD. Renal interstitial fibrosis is characterized by inflammation, extracellular matrix (ECM) deposition, epithelial-to-mesenchymal transition (EMT), and the activation and proliferation of fibroblasts and microvascular rarefaction [2]. The majority of studies have shown that transforming growth factor-β (TGF-β) plays a key role in fibrotic progression, which executes its biological function by activation of Smad signaling pathway [3]. TGF- β1, the most abundant isoform of TGF- β family members, can be secreted by infiltrated inflammatory ubiquinone coq10 and all types of renal cells. In turn, TGF-β1 acts on many types of cells in kidneys, including podocytes, tubular epithelia cells, macrophages or T cells [4]. Significantly, TGF-β1 is secreted in an inactive (latent) form in association with latency-associated peptide (LAP) and binds to latent TGF-β-binding protein (LTBP) in the target tissues. It could be easily activated by various stimuli including plasmin or reactive oxygen species (ROS), Then TGF-β1 can be released from the LAP and LTBP and becomes active form [5]. Renal tubular epithelial cells and fibroblasts can be activated by TGF-β1 to produce numerous ECM and inflammatory cytokines, which further lead to tubulointerstitial damage, interstitial inflammation, and eventually renal failure [6,7]. TGF- β1 can induce renal fibrosis via activation of both Smad-based and non-Smad-based signaling pathways, which result in activation of myofibroblasts, excessive production of ECM and inhibition of ECM degradation [8]. The principal effector cells responsible for the excessive deposition of ECM are the activated interstitial myofibroblasts [9,10]. Accumulating evidence implicates EMT as a major factor in the onset and pathogenesis of renal interstitial fibrosis [11,12]. EMT is a phenotypic transformation of renal tubular epithelial cells characterized by a loss of epithelial cell markers like E-cadherin, and a concurrent gain of mesenchymal features like α-smooth muscle actin (α-SMA) and vimentin [9,13]. Consequently, EMT and ECM deposition are the most significant and common features in the process of fibrosis [2]. Histone deacetylases (HDACs) could remove the acetyl groups from lysine residues in a variety of proteins, leading to the compaction of chromatin and resultant repression of gene transcription. In mammals, there are 18 HDACs grouped into four classes: class I HDACs (1, 2, 3 and 8), class II HDACs (4, 5, 6, 7, 9 and 10), class III HDACs (Sirt 1–7) and class IV (HDAC11) [14]. Pan-inhibitors of HDACs (i.e. Trichostatin A, vorinostat) play an important role in therapies to combat cancers [15,16]. Besides their anticancer activities, these pan-HDAC inhibitors also have inhibitory effects against tissue fibrosis in the heart [17,18], liver [[19], [20], [21]], and kidney [[22], [23], [24]], which presents the possibility of using HDACs as targets in the treatment of chronic fibrotic diseases. Trichostatin (TSA), a pan-HDAC inhibitor, has been proved that it could suppress TGF-β1-induced EMT in human renal epithelial cells [25]. And TSA also protects against renal ischemia reperfusion injury and fibrosis formation [26]. The report has suggested that global suppression of HDAC activities by inhibitors targeting both class I and class II HDACs inhibits TGF-β1-induced EMT in human renal proximal tubular epithelial cells [25]. However, it is very important to identify which isoform of HDAC is involved, since each HDAC appears to have a different function [27]. The roles and mechanisms of specific HDAC isoforms in the control of renal fibrosis remain unclear. Romidepsin (termed FK228), is a selective inhibitor of class I HDACs mainly acts on HDAC1 and HDAC2. The structure of FK288 is indicated in Fig. 1D. Emerging studies have shown that FK228 functions as a potent tumor suppressor and antitumor drug [[28], [29], [30]]. in vitro, FK228 has been shown to greatly inhibit the growth of several tumor cell types, including lymphomas [31,32], lung cancers [33], and prostate cancers [34]. Nevertheless, the effects of FK228 on renal interstitial fibrosis and the mechanism by which it works remain unclear.