CCN2 mediates fibroblast-macrophage interaction in knee arthrofibrosis based on single-cell RNA-seq analysis

Area of Science:

• Cell biology
• Immunology
• Biochemistry

Background:

• Knee arthrofibrosis is a debilitating condition marked by excessive matrix protein deposition, impairing daily function.
• The precise cellular mechanisms driving knee arthrofibrosis remain incompletely understood.

Purpose of the Study:

• To elucidate the cellular heterogeneity and molecular pathways involved in knee arthrofibrosis.
• To identify potential therapeutic targets for managing knee arthrofibrosis.

Main Methods:

• Combined flow cytometry and single-cell RNA sequencing on synovial tissues from patients with and without knee arthrofibrosis.
• Analysis of fibroblast-macrophage interactions and the role of the TGF-β pathway.
• Validation of CCN2 expression correlation with fibrosis markers and patient outcomes.

Main Results:

• Knee arthrofibrosis tissues showed increased macrophages and fibroblasts, with decreased fibroblast-like synoviocytes, endothelial cells, vascular smooth muscle cells, and T cells.
• Fibroblast-macrophage interaction, mediated by the TGF-β pathway, induced CCN2 expression in fibroblasts.
• CCN2 is essential for fibroblast activation, proliferation, and migration via the TGFBR/SMAD pathway.
• CCN2 expression correlated positively with collagen and TGF-β levels and negatively with patient-reported outcomes.

Conclusions:

• CCN2 plays a critical role in fibroblast-macrophage interactions driving fibrosis in knee arthrofibrosis through the TGF-β pathway.
• CCN2 emerges as a potential biomarker and therapeutic target for knee arthrofibrosis.