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METTL3 mediates osteoblast apoptosis by regulating endoplasmic reticulum stress during LPS-induced inflammation

Yiping Kong1, Yiwen Zhang1, Yongjie Cai1

  • 1Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China.

Cellular Signalling
|April 24, 2022
PubMed

Insights

METTL3 deficiency increases osteoblast apoptosis during inflammation by upregulating ER stress via YTHDF2 and Grp78. Restoring ER stress rescues osteoblast function, highlighting METTL3

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Osteoblast apoptosis disrupts skeletal homeostasis in inflammatory bone diseases.
  • METTL3 (methyltransferase-like 3) is crucial for osteogenic differentiation.
  • The role of METTL3 in osteoblast apoptosis under inflammation is unclear.

Purpose of the Study:

  • Investigate METTL3's function in osteoblast apoptosis during inflammation.
  • Elucidate the molecular mechanisms linking METTL3, ER stress, and osteoblast apoptosis.

Main Methods:

  • Analyzed METTL3 expression and m6A levels in osteoblasts.
  • Utilized METTL3 knockdown and LPS stimulation models.
  • Performed RNA-seq, Western blotting, and RIP-qPCR.
  • Assessed osteoblast apoptosis, proliferation, and differentiation markers.
  • Investigated the role of ER stress and YTHDF2.

Main Results:

  • METTL3 expression decreased with LPS stimulation, and its knockdown increased osteoblast apoptosis.
  • METTL3 knockdown reduced anti-apoptotic BCL-2 and increased cleaved Caspase-3, PARP-1, and Caspase-12.
  • METTL3 deficiency inhibited osteoblast proliferation, differentiation, ALP activity, and mineralized nodule formation.
  • METTL3 depletion upregulated ER stress markers (GRP78, ATF4, CHOP) and enhanced GRP78 expression via YTHDF2-mediated mRNA degradation.
  • Inhibition of ER stress rescued METTL3 knockdown-induced apoptosis and promoted osteoblast function.

Conclusions:

  • METTL3 knockdown promotes osteoblast apoptosis and impairs function under inflammatory conditions.
  • This occurs through enhanced ER stress mediated by YTHDF2-dependent Grp78 upregulation.
  • Targeting METTL3 or ER stress pathways may offer therapeutic strategies for inflammatory bone diseases.
Keywords:
ER stressMETTL3N6-methyladenosineapoptosismRNA stabilityosteoblast differentiation

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