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

N⁶-methyladenosine (m⁶A) modification is critically involved in regulating the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), yet the functional contributions of m⁶A 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 m⁶A 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.