SIS3 attenuates traumatic heterotopic ossification by targeting TGF-β2-driven endothelial-mesenchymal transition

Area of Science:

• Regenerative Medicine
• Molecular Biology
• Pathology

Background:

• Heterotopic ossification (HO) is a condition causing ectopic bone growth with few treatment options.
• Endothelial-mesenchymal transition (EndMT) is linked to HO, but its upstream regulators are unclear.

Purpose of the Study:

• To investigate the molecular mechanisms linking EndMT to traumatic HO.
• To identify potential therapeutic targets for HO treatment.

Main Methods:

• Integrated single-cell RNA sequencing data with in vitro and in vivo functional assays.
• Utilized genetic ablation, antibody neutralization, and small-molecule inhibitors (SIS3) in mouse models.

Main Results:

• TGF-β2 signaling via Smad2/3 promotes EndMT-like changes in endothelial cells, contributing to ectopic bone formation in HO.
• Blocking TGF-β2 or Smad3 phosphorylation with SIS3 significantly reduced HO development.
• TGF-β2 neutralization and Smad3 inhibition attenuated EndMT and subsequent ossification.

Conclusions:

• A TGF-β2-Smad2/3 signaling axis is proposed to drive EndMT-like plasticity in traumatic HO.
• Smad3-targeted interventions show promise for preventing HO and warrant further preclinical evaluation.