Negative Regulation of LINC01013 by METTL3 and YTHDF2 Enhances the Osteogenic Differentiation of Senescent Pre‐Osteoblast Cells Induced by Hydrogen Peroxide

Abstract Senescent pre‐osteoblasts have a reduced ability to differentiate, which leads to a reduction in bone formation. It is critical to identify the keys that regulate the differentiation fate of senescent pre‐osteoblasts. LINC01013 has an essential role in cell stemness, differentiation, and senescence regulation. This study aims to examine the role and mechanism of LINC01013 in regulating osteogenic differentiation in senescent human embryonic osteoblast cell line (hFOB1.19) cells induced by hydrogen peroxide (H 2 O 2 ). The results show that LINC01013 decreased alkaline phosphatase activity, mineralization of hFOB1.19 cells in vitro, and the expression of collagen II, osteocalcin, and bone sialoprotein. LINC01013 knockdown enhances the osteogenesis of hFOB1.19 cells and rescues osteogenic differentiation impaired by H 2 O 2 . METTL3 negatively regulates LINC01013 expression, enhancing hFOB1.19 cells' osteogenesis in vitro and in vivo. METTL3 overexpression can enhance hFOB1.19 cells' osteogenic differentiation impaired by H 2 O 2 . YTHDF2 promotes LINC01013 decay, facilitating osteogenic differentiation. YTHDF2 overexpression rescues hFOB1.19 cells osteogenic differentiation impaired by H 2 O 2 . Taken together, METTL3 upregulates osteogenic differentiation by inhibiting LINC01013, and YTHDF2 accelerates LINC01013 degradation, reducing its inhibitory effect. This study highlights LINC01013 as a key regulator in the fate switching process of senescent hFOB1.19 cells, impacting osteogenic differentiation.