ATF4 promotes bone angiogenesis by increasing VEGF expression and release in the bone environment

Area of Science:

• Bone biology
• Vascular biology
• Molecular signaling

Background:

• Activating transcription factor 4 (ATF4) is vital for bone remodeling.
• The role of ATF4 in bone angiogenesis remains unclear.
• Bone angiogenesis is essential for skeletal health and repair.

Purpose of the Study:

• To investigate the role of ATF4 in bone angiogenesis.
• To elucidate the molecular mechanisms by which ATF4 influences bone vascularization.
• To determine ATF4's regulation of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in osteoblasts.

Main Methods:

• Gene ablation of Atf4 in mice.
• In vivo and in vitro studies of skeletal vasculature and microvascular density.
• Analysis of HIF-1α and VEGF expression and stability.
• Co-immunoprecipitation assays to study protein interactions.
• Assessment of endothelial sprouting and osteoclast differentiation.

Main Results:

• Ablation of Atf4 severely impaired skeletal vasculature and reduced bone microvascular density.
• Loss of ATF4 decreased HIF-1α and VEGF expression in osteoblasts, compromising hypoxia-induced angiogenesis.
• ATF4 stabilizes HIF-1α by inhibiting its ubiquitination and proteasomal degradation.
• Parathyroid hormone-related protein (PTHrP) and RANKL promote VEGF release and angiogenesis via ATF4-dependent pathways.

Conclusions:

• ATF4 is a novel key regulator of the HIF/VEGF axis in osteoblasts during hypoxia.
• ATF4 plays a critical role in bone angiogenesis by stabilizing HIF-1α and promoting VEGF release.
• Targeting ATF4 may offer therapeutic strategies for bone vascularization disorders.