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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis
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Cbfβ governs osteoblast-adipocyte lineage commitment through enhancing β-catenin signaling and suppressing

Mengrui Wu1,2, Yiping Wang1,2, Jian-Zhong Shao1

  • 1Institute of Genetics, Life Science College, Zhejiang University, Hangzhou 310058, People's Republic of China.

Proceedings of the National Academy of Sciences of the United States of America
|September 3, 2017
PubMed

Insights

Core-binding factor subunit beta (Cbfβ) is crucial for maintaining osteoblast lineage commitment. Loss of Cbfβ in mice leads to severe osteoporosis and increased adipogenesis, highlighting Cbfβ

Area of Science:

  • * Stem Cell Biology
  • * Bone Biology
  • * Molecular Biology

Background:

  • The precise mechanisms governing transcription factor regulation of mesenchymal stem cell lineage commitment are not fully understood.
  • Core-binding factor subunit beta (Cbfβ) is a key transcription factor involved in various cellular processes, including bone development.

Purpose of the Study:

  • To elucidate the role of Cbfβ in the lineage commitment of osteoblasts.
  • To investigate the impact of Cbfβ deficiency on mesenchymal stem cell differentiation towards osteogenic and adipogenic lineages.

Main Methods:

  • Generation of three distinct mouse models with Cbfβ deletion at different osteoblast lineage stages (Prx1-Cre, Col2α1-Cre, Osx-Cre).
  • Analysis of bone phenotype, including bone mineral density and adipocyte accumulation.
  • In vitro studies using calvarial cells and bone marrow mesenchymal stem cells to assess adipogenic potential and gene expression.
  • Chromatin immunoprecipitation (ChIP) and luciferase assays to determine Cbfβ/RUNX2 binding to the Wnt10b promoter.

Main Results:

  • Cbfβ-deficient mice exhibited severe osteoporosis and increased marrow adipocyte accumulation, indicating a shift towards adipogenesis.
  • Cbfβ-deficient mesenchymal stem cells and calvarial cells showed significantly enhanced adipogenic potential.
  • Cbfβ deficiency impaired canonical Wnt signaling, with reduced Wnt10b expression, which was directly regulated by Cbfβ/RUNX2 binding to its promoter.
  • Cbfβ/RUNX2 was found to inhibit the expression of the adipogenic regulator c/ebpα at the transcriptional level.

Conclusions:

  • Cbfβ plays a dual role in maintaining osteoblast lineage commitment by promoting osteogenesis and suppressing adipogenesis.
  • Cbfβ acts both cell-autonomously (inhibiting adipogenic gene expression) and cell non-autonomously (enhancing Wnt signaling).
  • Cbfβ deficiency leads to osteoblast-to-adipocyte reprogramming, suggesting Cbfβ as a potential therapeutic target for osteoporosis.
Keywords:
CbfβWnt/β-cateninbone−fat interactionosteoblasttranscription factor

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