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Suppression of osteoclastogenesis through phosphorylation of eukaryotic translation initiation factor 2 alpha

Kazunori Hamamura1, Nancy Tanjung, Hiroki Yokota

  • 1Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, SL155, 723 West Michigan Street, Indianapolis, IN, 46202, USA, hamamurk@iupui.edu.

Journal of Bone and Mineral Metabolism
|March 29, 2013
PubMed

Insights

Elevated eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation stimulates bone formation and inhibits bone resorption by regulating ATF4 and NFATc1. This suggests eIF2α signaling as a therapeutic target for osteoporosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Bone Biology

Background:

  • Stress-induced phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) is a cellular response to various stresses.
  • The role of eIF2α signaling in bone cell development, particularly osteoclastogenesis, remains largely unexplored.
  • Bone cells are sensitive to environmental stresses that impact eIF2α phosphorylation levels.

Purpose of the Study:

  • To investigate the role of eIF2α-mediated signaling in osteoblast and osteoclast development.
  • To evaluate the effects of inhibiting eIF2α de-phosphorylation on bone cell differentiation.
  • To identify potential therapeutic targets for osteoporosis based on eIF2α signaling.

Main Methods:

  • Utilized salubrinal and guanabenz to inhibit eIF2α de-phosphorylation in RAW264.7 pre-osteoclasts and MC3T3 E1 osteoblast-like cells.
  • Assessed matrix deposition in osteoblasts and differentiation into multi-nucleated osteoclasts.
  • Employed RNA interference for partial silencing of eIF2α to confirm pathway involvement.

Main Results:

  • Salubrinal and guanabenz treatment stimulated osteoblast matrix deposition via activating transcription factor 4 (ATF4) upregulation.
  • These agents reduced nuclear factor of activated T cells c1 (NFATc1) expression, inhibiting osteoclast differentiation.
  • Partial eIF2α silencing partially reversed the inhibitory effect on NFATc1 expression.

Conclusions:

  • Elevated eIF2α phosphorylation stimulates osteoblastogenesis and inhibits osteoclastogenesis.
  • The regulation of ATF4 and NFATc1 by eIF2α is a key mechanism in bone cell development.
  • eIF2α-mediated signaling presents a potential therapeutic strategy for preventing bone loss in osteoporosis.

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