Mettl3-mediated m6A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis

Nat Commun. 2018 Nov 14;9(1):4772. doi: 10.1038/s41467-018-06898-4.


N6-methyladenosine (m6A) is the most abundant epigenetic modification in eukaryotic mRNAs and is essential for multiple RNA processing events during mammalian development and disease control. Here we show that conditional knockout of the m6A methyltransferase Mettl3 in bone marrow mesenchymal stem cells (MSCs) induces pathological features of osteoporosis in mice. Mettl3 loss-of-function results in impaired bone formation, incompetent osteogenic differentiation potential and increased marrow adiposity. Moreover, Mettl3 overexpression in MSCs protects the mice from estrogen deficiency-induced osteoporosis. Mechanistically, we identify PTH (parathyroid hormone)/Pth1r (parathyroid hormone receptor-1) signaling axis as an important downstream pathway for m6A regulation in MSCs. Knockout of Mettl3 reduces the translation efficiency of MSCs lineage allocator Pth1r, and disrupts the PTH-induced osteogenic and adipogenic responses in vivo. Our results demonstrate the pathological outcomes of m6A mis-regulation in MSCs and unveil novel epitranscriptomic mechanism in skeletal health and diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Adipogenesis / genetics
  • Adiposity / genetics
  • Animals
  • Bone Marrow
  • Bone Marrow Cells / metabolism
  • Cell Differentiation / genetics
  • Estrogens / deficiency
  • Gene Expression Regulation
  • Mesenchymal Stem Cells / metabolism*
  • Methylation
  • Methyltransferases / genetics*
  • Mice
  • Mice, Knockout
  • Osteogenesis / genetics
  • Osteoporosis / genetics*
  • Parathyroid Hormone / metabolism
  • RNA, Messenger / metabolism*
  • Receptor, Parathyroid Hormone, Type 1 / genetics
  • Receptor, Parathyroid Hormone, Type 1 / metabolism
  • Signal Transduction


  • Estrogens
  • PTH1R protein, mouse
  • Parathyroid Hormone
  • RNA, Messenger
  • Receptor, Parathyroid Hormone, Type 1
  • N-methyladenosine
  • Methyltransferases
  • Mettl3 protein, mouse
  • Adenosine