m6A Methylation Regulates Osteoblastic Differentiation and Bone Remodeling

Abstract

Osteoporosis is a prevalent bone disease of the aging population, which is characterized by a decrease in bone mass because of the imbalance of bone metabolism. Although the prevention and treatment of osteoporosis have been explored by different researchers, the mechanisms underlying osteoporosis are not clear exactly. N6 methyladenosine (m6A) is a methylated adenosine nucleotide, which functions through its interaction with the proteins called “writers,” “readers” and “erasers.” The epigenetic regulation of m6A has been demonstrated to affect mRNA processing, nuclear export, translation, and splicing. At the cellular level, m6A modification has been known to affect cell proliferation, differentiation, and apoptosis of bone-related cells, such as bone marrow mesenchymal stem cells (BMSC), osteoblasts, and osteoclasts by regulating the expression of ALP, Runx2, Osterix, VEGF, and other related genes. Furthermore, PTH/Pth1r, PI3K‐Akt, Wnt/β‐Catenin, and other signaling pathways, which play important roles in the regulation of bone homeostasis, are also regulated by m6A. Thus, m6A modification may provide a new approach for osteoporosis treatment. The key roles of m6A modification in the regulation of bone health and osteoporosis are reviewed here in this article.

Deciphering Obesity-Related Gene Clusters Unearths SOCS3 Immune Infiltrates and 5mC/m6A Modifiers in Ossification of Ligamentum Flavum Pathogenesis

“…m6A methylation has been documented to be the most pervasive internal mRNA modification in eukaryotes, which plays important roles in affecting RNA metabolism including RNA splicing, translation, stability, and translocation ( 41 ). Numerous studies demonstrated that regulators of m6A RNA methylation were involved in bone homeostasis and human osteogenesis diseases ( 42 – 44 ). More importantly, dysregulation of m6A has also been associated with the initiation and progression of spinal ligament ossification disorders.…”

Bioinformatics Analysis Identifies Potential Ferroptosis Key Genes in the Pathogenesis of Ankylosing Spondylitis

“…The PI3K-Akt signaling pathways also played important roles in the regulation of bone homeostasis, which was supposed to be regulated by N6 methyladenosine (m6A). At the cellular level, m6A modi cation has been known to affect cell proliferation, differentiation, and apoptosis of bonerelated cells, such as bone marrow mesenchymal stem cells (BMSC), osteoblasts, and osteoclasts by regulating the expression of ALP, Runx2, Osterix, VEGF, and other related genes [31] . Thus, m6A modi cation may also provide a new approach for AS treatment.…”

Effects of BMSC-Derived EVs on Bone Metabolism

“…At the RNA level, more than 100 post-transcriptional modifications have been identified, while m6A methylation is one of the most common modifications in mammals that regulate post-transcriptional gene expression without changing the base sequence [ 126 ]. m6A methylation is mainly involved in many biological processes and diseases through three types of proteins: methyltransferases, methylation readers and demethylases [ 127 ]. Among them, m6A demethylases, such as Alpha-ketoglutarate-dependent dioxygenase FTO (FTO), can remove m6A methylated groups in RNA, which is the basis for the dynamic reversibility of methylation [ 127 ].…”

“…m6A methylation is mainly involved in many biological processes and diseases through three types of proteins: methyltransferases, methylation readers and demethylases [ 127 ]. Among them, m6A demethylases, such as Alpha-ketoglutarate-dependent dioxygenase FTO (FTO), can remove m6A methylated groups in RNA, which is the basis for the dynamic reversibility of methylation [ 127 ]. FTO, also known as fat mass and obesity-associated protein, is one of the key elements in regulating body weight and fat mass, mainly by affecting lipogenesis [ 128 ].…”