A novel METTL3 inhibitor nimbolide ameliorates osteoporosis via orchestrating osteoclastogenesis in an m6A-dependent manner - PubMed
4 hours ago
- #Osteoporosis
- #METTL3
- #Nimbolide
- Osteoporosis (OP) is a chronic metabolic bone disease with limited effective therapies.
- METTL3 promotes osteoclast differentiation and bone erosion in OP, correlating with bone loss.
- Nimbolide (Nim) identified as a direct METTL3 inhibitor, disrupting its methyltransferase activity.
- Nim treatment suppresses osteoclastogenesis and attenuates OP in mice.
- METTL3 installs m6A on Lrp1 mRNA, leading to its degradation via YTHDF2, reducing anti-osteoclastogenic protein LRP1.
- Nim restores LRP1 levels by blocking METTL3-mediated m6A methylation, inhibiting osteoclast hyperactivity.
- AAV9-driven METTL3 overexpression reverses Nim's efficacy in OVX mice.
- Nim protects against OP via the METTL3-m6A-YTHDF2-LRP1 axis, suggesting a new therapeutic strategy.