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FOXOs attenuate bone formation by suppressing Wnt signaling

Srividhya Iyer1, Elena Ambrogini, Shoshana M Bartell

  • 1Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA.

The Journal of Clinical Investigation
|July 23, 2013
PubMed

Insights

Deleting FOXO transcription factors in bone progenitor cells increases bone mass and reduces fat in aging mice. This suggests FOXO activation contributes to age-related bone loss and osteoporosis.

Area of Science:

  • Bone biology
  • Cellular signaling
  • Aging research

Background:

  • Wnt/β-catenin/TCF signaling is crucial for bone formation and inhibits fat development.
  • Aging leads to reduced bone formation and increased bone marrow fat, associated with oxidative stress and FOXO transcription factor activation.
  • FOXO factors suppress Wnt signaling by redirecting β-catenin activity.

Purpose of the Study:

  • To investigate the role of FOXO transcription factors in regulating bone mass and marrow adiposity during aging.
  • To determine if FOXO factors restrain Wnt/β-catenin signaling in bone progenitor cells.

Main Methods:

  • Mice lacking Foxo1, -3, and -4 in Osterix1-expressing progenitors were analyzed.
  • Bone mass, osteoblast number, and bone marrow adiposity were assessed in aged mice.
  • Wnt/β-catenin signaling, cyclin D1 expression, and cell proliferation were examined in Foxo-deficient cells.

Main Results:

  • Mice lacking Foxo1, -3, and -4 showed increased osteoblast number and high bone mass, maintained in old age.
  • These mice also exhibited reduced bone marrow adiposity with aging.
  • Increased bone mass was linked to enhanced osteoprogenitor proliferation and bone formation via Wnt/β-catenin signaling and cyclin D1 upregulation.
  • Deletion of β-catenin in Foxo-null cells abolished these effects.

Conclusions:

  • FOXO transcription factors restrain Wnt signaling in bone progenitor cells.
  • FOXO activation by age-associated stressors may drive osteoporosis development.
  • Targeting FOXO signaling could be a therapeutic strategy for age-related bone loss.

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