Radiation Induces Bone Microenvironment Disruption by Activating the STING-TBK1 Pathway

Area of Science:

• Bone Biology
• Radiotherapy Research
• Cellular Signaling

Background:

• Therapeutic irradiation (IR) can damage normal bone tissue, causing bone loss and promoting tumor metastasis.
• IR-induced disruption of the bone microenvironment is a significant clinical concern.
• Understanding the cellular mechanisms is crucial for preventing radiotherapy-associated adverse effects.

Purpose of the Study:

• To explore the cellular regulatory mechanism of IR-induced bone microenvironment disruption.
• To investigate the role of the stimulator of interferon genes (STING) pathway in radiation-induced bone damage.
• To identify potential therapeutic targets for mitigating radiotherapy-associated bone loss.

Main Methods:

• Established local IR mouse models and in vitro osteocyte (OCY) models.
• Analyzed multicellular biological injuries and cellular senescence following irradiation.
• Utilized small interfering RNA (siRNA) and a STING inhibitor (C-176) to probe the STING pathway's role.

Main Results:

• Local IR induced OCY dysfunction, osteoclastogenesis activation, osteogenesis degeneration, and cellular senescence.
• Irradiation significantly elevated STING expression, P-TBK1, RANKL, and SOST levels.
• STING inhibition via siRNA or C-176 mitigated IR-induced osteoclastogenesis and protected against bone damage.

Conclusions:

• The STING-P-TBK1 signaling pathway is critical in regulating inflammatory cytokine secretion and osteoclastogenesis in IR-induced bone microenvironment disruption.
• Selective STING antagonists show potential for repairing IR-induced multicellular damage and rebalancing bone metabolism.
• Targeting the STING pathway offers a promising strategy to prevent radiotherapy-associated adverse effects on bone.