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METTL3 Modulates Osteoclast Differentiation and Function by Controlling RNA Stability and Nuclear Export
Di Li, Luhui Cai, Runsha Meng1
1Guanghua School of Stomatology & Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Ling Yuan Xi Road, Guangzhou 510055, China.
International Journal of Molecular Sciences
|March 4, 2020
Summary
The study reveals that METTL3, an enzyme involved in RNA modification, is crucial for osteoclast differentiation and function. METTL3 regulates bone homeostasis by controlling specific gene expression and signaling pathways essential for osteoclast development.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Osteoclast differentiation and function are vital for bone homeostasis.
- N6-methyladenosine (m6A) modification regulates cell lineage differentiation.
- The role of m6A in osteoclast differentiation was previously unknown.
Purpose of the Study:
- To investigate the effect of m6A modification on osteoclast differentiation.
- To elucidate the role of methyltransferase METTL3 in osteoclast biology.
Main Methods:
- Observed m6A levels and METTL3 expression during osteoclast differentiation.
- Utilized Mettl3 knockdown in osteoclast precursors.
- Analyzed osteoclast-specific gene expression, bone-resorbing activity, and signaling pathways (MAPK, NF-κB, PI3K-AKT).
- Investigated mRNA stability and nuclear export of Traf6 and Atp6v0d2.
Main Results:
- Mettl3 knockdown increased osteoclast size but decreased bone-resorbing ability.
- Mettl3 depletion inhibited osteoclast-specific genes (Nfatc1, c-Fos, Ctsk, Acp5, Dcstamp) but upregulated fusion gene Atp6v0d2.
- METTL3 deficiency reduced MAPK, NF-κB, and PI3K-AKT signaling.
- Mettl3 depletion led to Traf6 mRNA retention in the nucleus and reduced TRAF6 protein.
Conclusions:
- METTL3 plays a critical role in osteoclast differentiation and function.
- METTL3 regulates Atp6v0d2 mRNA stability via YTHDF2 and Traf6 mRNA nuclear export.
- These findings reveal the molecular mechanisms of RNA epigenetic regulation in osteoclast development.
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