C/EBPβ Contributes to Cancer‐Induced Bone Pain by Inhibiting CD200/CD200R1 in the Spinal Cord

TL;DR

This study finds that C/EBPβ contributes to cancer-induced bone pain by inhibiting CD200/CD200R1 signaling in the spinal cord, suggesting a new therapeutic target.

Contribution

The study identifies c/EBPβ as a novel regulator of CD200R1 in microglia-mediated neuroinflammation linked to cancer-induced bone pain.

Findings

CD200/CD200R1 signaling is inhibited in the spinal cord of CIBP mice.

Knockdown of c/EBPβ restores CD200R1 levels and reduces pain behaviors in CIBP mice.

Overexpression of CD200R1 alleviates neuroinflammation and pain in CIBP mice.

Abstract

Advanced cancer patients still suffer from devastating bone pain, with less efficacious treatments. The spinal microglia activation and neuroinflammation are the pivotal pathological processes of cancer‐induced bone pain (CIBP). This study aims to explore whether c/EBPβ negatively regulates CD200R1 to induce microglia‐medicated neuroinflammation in the spinal cord of CIBP mice.

The CIBP mice model was constructed by intrafemoral injection of Lewis lung cancer cells to investigate the role of CD200/CD200R1 signaling and their upstream molecule CCAAT/enhancer binding protein β (c/EBPβ) in CIBP. Mechanical allodynia and thermal hyperalgesia were evaluated by von Frey filaments and hot plate, respectively. Adeno‐associated viruses were constructed to regulate the expression of CD200R1 and c/EBPβ. The protein level was assessed by western blotting, and microglia activation was detected by immunofluorescence.

Our results showed that CD200/CD200R1 signaling was inhibited in the spinal cord of CIBP mice. Intrathecal injection of CD200R1 agonist CD200Fc effectively reversed the nociceptive behaviors in CIBP mice. Overexpression of CD200R1 could also effectively ameliorate the pain behaviors and spinal neuroinflammation in CIBP mice. Transcription factor c/EBPβ was upregulated in the spinal cord of CIBP mice. Knockdown of c/EBPβ effectively inhibited the microglia‐mediated neuroinflammation by restoring CD200R1 protein levels, alleviating pain behavior in CIBP mice.

c/EBPβ‐mediated suppression of the CD200/CD200R1 signaling pathway represents one potential mechanism in promoting microglial activation and neuroinflammation in the spinal cord of CIBP mice, which provides a potential therapeutic target for CIBP management.

Patients with advanced cancer continue to endure severe bone pain, for which current therapeutic options remain inadequate. Spinal microglial activation and subsequent neuroinflammation constitute key pathological mechanisms underlying cancer‐induced bone pain (CIBP). This study identified that elevated c/EBPβ suppresses the CD200/CD200R1 signaling pathway and induces microglia activation and neuroinflammatory responses in the spinal cord, thereby contributing to the initiation and maintenance of CIBP.

Figures