Regulatory Role of RNA N6-Methyladenosine Modification in Bone Biology and Osteoporosis

Luo

et al. 2021

Preprint

Background: Bone morphogenetic protein 9 (BMP9) is one of excellent osteogenic factors, but it can also initiate adipogenesis concomitantly. Thus, the osteogenic potential of BMP9 may be enhanced if the adipogenesis were reduced. It was reported that lysyl oxidase (Lox) may function as a critical switcher for adipogenesis. Up to date, the role of Lox in BMP9-induced osteoblastic differentiation remains unknown.Methods: The effect and possible mechanism of Lox on the osteogenic function of BMP9 were evaluated with RT-PCR, western blotting, immunofluorescent and histochemical staining. The same results were also confirmed with the in vivo BMP9-induced ectopic bone formation model.Results: The mRNA and protein of Lox are both detectable in progenitor cells, and it was increased by BMP9 in 3T3-L1 cells. BMP9-induced Runx2, OPN and mineralization were all enhanced by inhibiting or silencing Lox, but reduced by exogenous Lox. BMP9 increased the mRNA level of c-Myc, which was enhanced by inhibiting Lox, so did the protein level of β-catenin. Effects of Lox specific inhibitor on BMP9-induced Runx2, OPN and mineralization were reduced obviously by silencing β-catenin. HIF-1α was up-regulated by BMP9, which was enhanced by inhibiting or silencing Lox, but decreased by Lox over-expression. The effects of Lox specific inhibitor on increasing BMP9-induced osteogenic markers were reduced greatly by silencing HIF-1α. On the contrary, the inhibitory effect of Lox on BMP9-induced osteoblastic markers was almost abolished by HIF-1α over-expression. BMP9-induced bone formation was increased by silencing Lox or over-expressing HIF-1α. The effect of silencing Lox on potentiating BMP9-induced bone formation was attenuated by silencing HIF-1α. Lox specific inhibitor increased the level of β-catenin and decreased that of SOST, but these effects were almost reversed by silencing HIF-1α.Conclusions: Lox may reducing the osteoblastic-induction function of BMP9 through inhibiting Wnt/β-catenin signal via down-regulation of HIF-1α partly.

Section: Discussionmentioning

confidence: 99%

Lysyl Oxidase Down-Regulates The Osteoblastic Potential of BMP9 Through Inhibiting HIF-1α/Wnt/β-Catenin Axis in Mesenchymal Stem Cells

Luo

et al. 2021

Preprint

“…Several other psychiatric disorders, such as Alzheimer’s disease or Parkinson’s disease, were associated with altered m6A modifications [ 112 , 113 , 114 ]. Moreover, many research papers report that m6A methylome exerts its role in nutritional physiology and metabolism [ 115 , 116 ], osteogenic differentiation [ 117 , 118 ] or cardiovascular system homeostasis [ 119 , 120 ].…”

Section: New Epigenetic Player—m6a Modifications Of Rnamentioning

confidence: 99%

m6A RNA Methylation in Systemic Autoimmune Diseases—A New Target for Epigenetic-Based Therapy?

Wardowska

2021

Pharmaceuticals

The general background of autoimmune diseases is a combination of genetic, epigenetic and environmental factors, that lead to defective immune reactions. This erroneous immune cell activation results in an excessive production of autoantibodies and prolonged inflammation. During recent years epigenetic mechanisms have been extensively studied as potential culprits of autoreactivity. Alike DNA and proteins, also RNA molecules are subjected to an extensive repertoire of chemical modifications. N6-methyladenosine is the most prevalent form of internal mRNA modification in eukaryotic cells and attracts increasing attention due to its contribution to human health and disease. Even though m6A is confirmed as an essential player in immune response, little is known about its role in autoimmunity. Only few data have been published up to date in the field of RNA methylome. Moreover, only selected autoimmune diseases have been studied in respect of m6A role in their pathogenesis. In this review, I attempt to present all available research data regarding m6A alterations in autoimmune disorders and appraise its role as a potential target for epigenetic-based therapies.

Stem Cells International

“…Even so, the biological activity of MSCs in a normal bone is closely related to RNA N 6 -methyladenosine (m 6 A) modification. Osteogenesis induced by methyltransferase like 3 (METTL3) is counterbalanced with lipogenesis promoted by demethyltransferase fat mass and obesity-associated protein (FTO) [ 61 ]. During the aging process, expression of Fto gene increases and inhibits m 6 A formation on Pparγ mRNA, which results in lipogenesis through the GDF11-FTO-PPAR γ axis [ 62 ].…”

Section: Epigenetic Regulation In Msc Aging and Osteoporosismentioning

confidence: 99%

Epigenetic Regulation in Mesenchymal Stem Cell Aging and Differentiation and Osteoporosis

Wang

Zhu

et al. 2020

Mesenchymal stem cells (MSCs) are a reliable source for cell-based regenerative medicine owing to their multipotency and biological functions. However, aging-induced systemic homeostasis disorders in vivo and cell culture passaging in vitro induce a functional decline of MSCs, switching MSCs to a senescent status with impaired self-renewal capacity and biased differentiation tendency. MSC functional decline accounts for the pathogenesis of many diseases and, more importantly, limits the large-scale applications of MSCs in regenerative medicine. Growing evidence implies that epigenetic mechanisms are a critical regulator of the differentiation programs for cell fate and are subject to changes during aging. Thus, we here review epigenetic dysregulations that contribute to MSC aging and osteoporosis. Comprehending detailed epigenetic mechanisms could provide us with a novel horizon for dissecting MSC-related pathogenesis and further optimizing MSC-mediated regenerative therapies.