Abstract
As a systemic disease, osteoporosis (OP) results in bone density loss and fracture risk, particularly in the hip and vertebrae. However, the underlying molecular mechanisms of OP development have not been fully illustrated. N6-Methyladenosine (m6A) is the most abundant modification of mRNAs, which is involved in many of pathological processes in aging disease. However, its role and regulatory mechanism in OP remains unknown. Here, we aimed to investigate the roles of m6A and its demethylase FTO in OP development. The results showed that m6A methylated RNA level was up-regulated in the bone marrow mesenchymal stem cells (BMSCs) from patients with OP. The level of N6-methyladenosine demethylase FTO was consistently decreased in the BMSCs from patients with OP. Functionally, lentivirus-mediated FTO overexpression in normal BMSCs to compromised osteogenic potential. Mechanism analysis further suggested that FTO overexpression decreased the m6A methylated and total level of runt related transcription factor 2 (Runx2) mRNA, subsequently inhibited osteogenic differentiation. We found that FTO inhibition could effectively improve the bone formation in ovariectomized osteoporotic mice in vivo. Together, these results reveal that RNA N6-methyladenosine demethylase FTO promotes osteoporosis through demethylating runx2 mRNA and inhibiting osteogenic differentiation.
Highlights
Osteoporosis (OP) is a common bone disease regardless of gender [1], which is characterized by low bone mass and damaged bone structure, which can lead to increased risk of fracture [2]
The level of methyltransferase FTO is elevated in bone marrow mesenchymal stem cells (BMSCs) from OP patients and OVX mouse To understand the role of m6A in OP, we evaluated the total methylated m6A RNA levels in human BMSCs
These results showed that the mRNA level of FTO was significantly elevated in OP-BMSCs (Figure 1B)
Summary
Osteoporosis (OP) is a common bone disease regardless of gender [1], which is characterized by low bone mass and damaged bone structure, which can lead to increased risk of fracture [2]. It is well documented that the abnormal lineage differentiation of endogenous BMSCs leads to osteoporosis [6]. N6-Methyladenosine (m6A) modification, which is catalyzed by a methyltransferase complex including of METTL3, METTL14 and their cofactors [7], WTAP, VIRMA, and RBM15 [8], is one of the most common modifications of mRNAs in eukaryotes [9, 10]. It is usually reversed by two mammalian RNA demethylases, ALKBH5 and FTO [11, 12]. The actual roles and underlying molecular basis of FTO in the osteogenic differentiation disorders of BMSCs and the OP development remains unknown
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