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(2020) 11:456

REVIEW

Open Access

Epidrugs: novel epigenetic regulators that open a new window for targeting osteoblast differentiation Mahsa Ghorbaninejad1,2,3†, Maliheh Khademi-Shirvan2,3†, Samaneh Hosseini2,4* and Mohamadreza Baghaban Eslaminejad2*

Abstract Efficient osteogenic differentiation of mesenchymal stem cells (MSCs) is a critical step in the treatment of bone defects and skeletal disorders, which present challenges for cell-based therapy and regenerative medicine. Thus, it is necessary to understand the regulatory agents involved in osteogenesis. Epigenetic mechanisms are considered to be the primary mediators that regulate gene expression during MSC differentiation. In recent years, epigenetic enzyme inhibitors have been used as epidrugs in cancer therapy. A number of studies mentioned the role of epigenetic inhibitors in the regulation of gene expression patterns related to osteogenic differentiation. This review attempts to provide an overview of the key regulatory agents of osteogenesis: transcription factors, signaling pathways, and, especially, epigenetic mechanisms. In addition, we propose to introduce epigenetic enzyme inhibitors (epidrugs) and their applications as future therapeutic approaches for bone defect regeneration. Keywords: Epigenetic, Epidrug, Mesenchymal stem cell, Osteoblast

Background Mesenchymal stem cells (MSCs) are considered to be potent tools for regenerative medicine, tissue engineering, and cellbased therapy because of their tri-lineage differentiation, selfrenewal potential, low immunogenicity, decreased risk for tumorigenicity, capability for expansion, and ease of accessibility [1]. During bone homeostasis and bone fracture repair, MSCs differentiate into osteoblasts that ultimately result in bone formation and regeneration. However, the application of MSCs in cell-based therapy may present challenges, such as unexpected differentiation of MSCs in different in vivo situations and low survival of MSCs after transplantation. * Correspondence: [email protected]; [email protected] † Mahsa Ghorbaninejad and Maliheh Khademi-Shirvan contributed equally to this work. 2 Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran Full list of author information is available at the end of the article

Thus, it is necessary to have a better understanding of the osteogenesis process and its exact regulatory mechanism [2, 3]. The process of osteogenic differentiation of MSCs is largely controlled by successive changes in the pattern of gene expression related to osteogenesis. Osteoblast differentiation of MSCs is highly modulated by cross-talk between genes, transcription factors, signaling pathways, and epigenetic mechanisms [4]. Epigenetic modulators alter chromatin architecture and change accessibility of genes to transcription factors and other regulators. These changes are largely responsible for the up- and downregulation of specific genes during a cell’