2. Academic Validation
  3. METTL3-mediated m6A modification of SOX4 regulates osteoblast proliferation and differentiation via YTHDF3 recognition

METTL3-mediated m6A modification of SOX4 regulates osteoblast proliferation and differentiation via YTHDF3 recognition

  • Cell Signal. 2024 Jan 7:115:111038. doi: 10.1016/j.cellsig.2024.111038.
Zhi-Wei Feng 1,  Bo Peng 2,  Sheng-Hong Wang 3,  Da-Cheng Zhao 4,  Yao-Bin Wang 5,  Ao Yang 6,  Hong-Wei Zhan 7,  Xiao-Yun Sheng 8,  Li-Hu Xu 9,  Xiao-Jun Ren 10,  Fei Yang 11,  Bin Geng 12,  Ya-Yi Xia 13
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China; Department of Orthopaedics, Nanchong Central Hospital, The Second Clinical Institute of North Sichuan Medical College, Nanchong, China. Electronic address: fengzhw20@lzu.edu.cn.
  • 2 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China. Electronic address: bpeng1990@163.com.
  • 3 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China. Electronic address: wangshh15@lzu.edu.cn.
  • 4 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China. Electronic address: zhaodacheng09@163.com.
  • 5 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China. Electronic address: 348776369@qq.com.
  • 6 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China.
  • 7 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China. Electronic address: zhanhw16@163.com.
  • 8 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China. Electronic address: shengxy20@lzu.edu.cn.
  • 9 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China. Electronic address: lanzhouxu@126.com.
  • 10 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China. Electronic address: renxj20@lzu.edu.cn.
  • 11 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China; Department of Orthopaedics, Nanchong Central Hospital, The Second Clinical Institute of North Sichuan Medical College, Nanchong, China.
  • 12 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China. Electronic address: ery_gengb@lzu.edu.cn.
  • 13 Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China; Gansu Province Orthopaedic Clinical Medicine Research Center, Lanzhou, China; Gansu Province Intelligent Orthopedics Industry Technology Center, Lanzhou, China. Electronic address: xiayy@lzu.edu.cn.
PMID: 38195035 DOI: 10.1016/j.cellsig.2024.111038
Abstract

N6-methyladenosine (m6A), the most prevalent internal modification in mRNA, is related to the pathogenesis of osteoporosis (OP). Although methyltransferase Like-3 (METTL3), an m6A transferase, has been shown to mitigate OP progression, the mechanisms of METTL3-mediated m6A modification in osteoblast function remain unclear. Here, fluid shear stress (FSS) induced osteoblast proliferation and differentiation, resulting in elevated levels of METTL3 expression and m6A modification. Through Methylated RNA Immunoprecipitation Sequencing (MeRIP-seq) and Transcriptomic RNA Sequencing (RNA-seq), SRY (Sex Determining Region Y)-box 4 (SOX4) was screened as a target of METTL3, whose m6A-modified coding sequence (CDS) regions exhibited binding affinity towards METTL3. Further functional experiments demonstrated that knockdown of METTL3 and SOX4 hampered osteogenesis, and METTL3 knockdown compromised SOX4 mRNA stability. Via RNA immunoprecipitation (RIP) assays, we further confirmed the direct interaction between METTL3 and SOX4. YTH N6-Methyladenosine RNA Binding Protein 3 (YTHDF3) was identified as the m6A reader responsible for modulating SOX4 mRNA and protein levels by affecting its degradation. Furthermore, in vivo experiments demonstrated that bone loss in an ovariectomized (OVX) mouse model was reversed through the overexpression of SOX4 mediated by adeno-associated virus serotype 2 (AAV2). In conclusion, our research demonstrates that METTL3-mediated m6A modification of SOX4 plays a crucial role in regulating osteoblast proliferation and differentiation through its recognition by YTHDF3. Our research confirms METTL3-m6A-SOX4-YTHDF3 as an essential axis and potential mechanism in OP.

Keywords

M(6)A modification; METTL3; Osteoporosis; SOX4; YTHDF3.

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