2. Academic Validation
  3. METTL3-mediated modification of SIRT1 m6A methylation protects osteoblasts from TBHP-induced senescence and promotes osteoblast proliferation

METTL3-mediated modification of SIRT1 m6A methylation protects osteoblasts from TBHP-induced senescence and promotes osteoblast proliferation

  • Chem Biol Interact. 2025 Oct 22:420:111672. doi: 10.1016/j.cbi.2025.111672.
Yi Chen 1,  Yaobin Wang 2,  Hefang Xiao 1,  Fei Teng 1,  Ao Yang 1,  Jinmin Liu 1,  Zirui Liu 1,  Xiaoyun Sheng 1,  Chengjun Zhang 1,  Shifeng Zhang 1,  Bin Geng 3,  Yayi Xia 4
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, 730000, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, 730000, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, 730000, China.
  • 2 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, 730000, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, 730000, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, 730000, China; The Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
  • 3 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, 730000, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, 730000, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, 730000, China. Electronic address: ldeygb2008@126.com.
  • 4 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, 730000, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, 730000, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, 730000, China. Electronic address: xyylzu@126.com.
PMID: 40716628 DOI: 10.1016/j.cbi.2025.111672
Abstract

The condition of age-related osteoporosis involves more senescent osteoblasts and a significant decline in osteoblast proliferation within the bone microenvironment. Methyltransferase 3 (METTL3), a key methylating enzyme, has been previously described as alleviating osteoporosis associated with estrogen deficiency. However, METTL3-mediated m6A modification in age-related osteoporosis remains unclear, as does its regulatory mechanism in osteoblasts. Our study revealed significant downregulation of METTL3 and m6A modification levels in femoral tissues of aged mice. In osteoblasts subjected to tert-butyl hydroperoxide (TBHP)-induced senescence, both METTL3 and m6A modification levels were markedly decreased. Functional assays revealed that knockdown of METTL3 and SIRT1 led to heightened osteoblast senescence and reduced proliferation, with METTL3 knockdown further compromising SIRT1 stability. Overexpression of METTL3 inhibited osteoblast senescence and enhanced proliferation under TBHP exposure. Furthermore, using RIP and MeRIP-qPCR assays, we confirmed that SIRT1 mRNA is directly targeted by METTL3-mediated m6A modification. Mechanistically, METTL3 enhanced SIRT1 mRNA stability via m6A modification, thereby inhibiting osteoblast senescence and promoting proliferation. YTHDF2 has been recognized as an m6A-recognizing protein that affects SIRT1 mRNA stability. Additionally, METTL3 overexpression significantly increased bone mass in aged mice, an effect absent in young mice. Our findings confirmed the important function of METTL3-mediated SIRT1 mRNA modification in modulating osteoblast senescence and proliferation via YTHDF2 recognition. Our results confirm that the METTL3-m6A-SIRT1-YTHDF2 is an important axis and mechanism in age-related osteoporosis.

Keywords

Age-related osteoporosis; METTL3; Osteoblast; SIRT1; YTHDF2.

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