Fig. 7
Schematic representation of the molecular mechanism underlying knee arthrofibrosis. Human synovial tissues from patients with knee arthrofibrosis (AF) and negative controls (NC) were obtained. First, with the FCM and single-cell transcriptomic analysis, we identified fibroblasts, macrophages, FLS, endothelial cells, VSMC, and T cells as main components of synovial tissues. The fibroblast-macrophage interactions were investigated, and CCN2 in the TGF-β pathway was identified as a potential biomarker for knee AF. Second, in vitro experimentations revealed that autocrine of CCN2 is essential in the pro-fibrotic functions (activation, proliferation, and migration) of fibroblasts through TGFBR/SMAD pathway. Then, we verified CCN2 expression in clinical patients and discovered that TGF-β induced CCN2 is positively related to AF. Schematic molecular mechanism underlying the knee arthrofibrosis is shown at the bottom. Macrophages initiate the fibrotic casade by activating multiple pro-fibrotic pathways, including TGF-β signaling pathways and others (the ncWnt, tenascin, and FGF signaling pathways). The fibroblasts, as receivers, affect macrophages via the CXCL signaling pathway. Additionally, autocrine of CCN2 by fibroblasts promoted fibrosis through TGFBR/SMAD pathway, thus leading to the knee arthrofibrosis
