YTHDF3 Enhances Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in Osteoporosis by Promoting TBX19 Expression

ABSTRACT N 6 ‐methyladenosine (m 6 A) modification is critically involved in regulating the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), yet the functional contributions of m 6 A reader proteins in osteoporosis remain poorly defined. In this study, we found that osteoporosis in rats correlates with severe bone loss and diminished osteogenic potential of BMSCs, accompanied by down‐regulation of the m 6 A reader YTHDF3. Functional assays showed that YTHDF3 promotes osteogenic differentiation of BMSCs. RNA‐sequencing analysis identified the transcription factor TBX19 as a key downstream mediator of YTHDF3. Subsequent investigations confirmed that Tbx19 knockdown not only attenuated the osteogenic capacity of BMSCs but also abrogated the pro‐osteogenic effect of Ythdf3 overexpression. Moreover, in vivo experiments demonstrated that Ythdf3 overexpression enhances the bone‐forming ability of osteoporotic BMSCs. Collectively, our results reveal that YTHDF3 acts as a positive regulator of BMSC osteogenesis, largely through regulating TBX19, and that its down‐regulation contributes to osteoporotic pathogenesis. These findings propose YTHDF3 as a novel potential therapeutic target for the treatment of osteoporosis.