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Atf4 regulates chondrocyte proliferation and differentiation during endochondral ossification by activating Ihh

Weiguang Wang1, Na Lian, Lingzhen Li

  • 1Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, 1225F Medical Research Building IV, Nashville, TN 37232, USA.

Development (Cambridge, England)
|November 13, 2009
PubMed

Insights

Activating transcription factor 4 (Atf4) is crucial for bone growth. Loss of Atf4 impairs chondrocyte proliferation and Indian hedgehog (Ihh) signaling, leading to skeletal defects.

Area of Science:

  • Skeletal Biology
  • Molecular Endocrinology
  • Developmental Biology

Background:

  • Activating transcription factor 4 (Atf4) is a CREB family transcription factor.
  • Atf4 plays a role in skeletal development, as evidenced by severe defects in Atf4 knockout mice.

Purpose of the Study:

  • To investigate the role of Atf4 in endochondral ossification.
  • To elucidate the molecular mechanisms by which Atf4 regulates chondrocyte function and bone growth.

Main Methods:

  • Analysis of Atf4 knockout mouse models.
  • Assessment of growth plate structure and chondrocyte differentiation markers.
  • ChIP assays to determine Atf4 binding to the Ihh promoter.
  • Pharmacological manipulation of Hedgehog signaling in mouse limb explants.

Main Results:

  • Atf4 ablation in mice resulted in delayed ossification, short stature, and limb shortening.
  • Atf4 deficiency disrupted growth plate columnar structure and reduced Indian hedgehog (Ihh) expression.
  • Atf4 directly binds to the Ihh promoter and activates its transcription.
  • Pharmacological reactivation of Hedgehog signaling rescued Atf4(-/-) chondrocyte proliferation and limb length defects.

Conclusions:

  • Atf4 is a critical transcriptional activator of Ihh in chondrocytes.
  • Atf4 regulates longitudinal bone growth by controlling chondrocyte proliferation and differentiation via Ihh signaling.

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