RNA N6-methyladenosine demethylase FTO promotes osteoporosis through demethylating Runx2 mRNA and inhibiting

Jing Wang1,2, Qiang Fu3, Jian Yang2

  • 1Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Aging
|September 8, 2021
PubMed

Insights

The N6-methyladenosine (m6A) demethylase FTO promotes osteoporosis by decreasing Runx2 mRNA levels, inhibiting bone formation. Inhibiting FTO improves bone density in osteoporosis models.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Osteoporosis (OP) is a systemic disease causing bone density loss and increased fracture risk.
  • The molecular mechanisms underlying OP development are not fully understood.
  • N6-methyladenosine (m6A) modification is implicated in aging diseases, but its role in OP is unknown.

Purpose of the Study:

  • To investigate the roles of m6A and its demethylase FTO in osteoporosis development.
  • To elucidate the regulatory mechanisms of FTO in bone metabolism.

Main Methods:

  • Analysis of m6A levels and FTO expression in bone marrow mesenchymal stem cells (BMSCs) from OP patients.
  • Overexpression of FTO in normal BMSCs using lentivirus.
  • Assessment of osteogenic differentiation potential.
  • In vivo studies using ovariectomized osteoporotic mice.

Main Results:

  • m6A RNA levels were elevated, while FTO levels were decreased in BMSCs from OP patients.
  • FTO overexpression in normal BMSCs compromised osteogenic potential.
  • FTO overexpression reduced m6A-modified and total Runx2 mRNA levels, inhibiting osteogenic differentiation.
  • FTO inhibition improved bone formation in vivo in an OP mouse model.

Conclusions:

  • RNA N6-methyladenosine demethylase FTO promotes osteoporosis.
  • FTO exerts its effect by demethylating Runx2 mRNA and inhibiting osteogenic differentiation.
  • Targeting FTO may offer a therapeutic strategy for osteoporosis.

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