Ednrb-driven ET-1/RXFP1 underlies TXA-induced exacerbation of acute cartilage injury-related PTOA.

OBJECTIVE

To investigate the role of endothelin receptor B (Ednrb/ETB) in tranexamic acid (TXA)-induced post-traumatic osteoarthritis (PTOA) and to elucidate the underlying molecular mechanisms.

METHODS

Adult rats were assigned to four groups: control + TXA (T), cartilage scratch + TXA (CT), subchondral fracture + TXA (ST), and combined cartilage-subchondral fracture + TXA (CST). RNA sequencing combined with Venn analysis was used to identify candidate genes, including Ednrb. Molecular docking was performed to evaluate the binding affinity between TXA and ETB. Rats were subsequently regrouped for histological, immunohistochemical, and biochemical analyses of cartilage. ATDC5 chondrocytes were transfected with si-Ednrb-1/2 and co-treated with TXA to assess cell viability and pathway activation.

RESULTS

RNA sequencing identified Ednrb as a core upregulated gene in the CT and CST groups. Molecular docking demonstrated strong binding between TXA and ETB (binding energy: -5.1 kcal/mol). In the rat PTOA model, TXA significantly increased OARSI scores in the NCT and NCST groups (P < 0.0001), upregulating the expression of ETB, matrix metalloproteinase 13 (MMP13), RXFP1, endothelin-1 (ET-1), phosphorylated nuclear factor-kappa B, and phosphorylated AKT, as well as the inflammatory mediators interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6. In ATDC5 cells, Ednrb knockdown significantly increased cell viability, reduced apoptosis, and downregulated ETB, MMP13, and pathway-related signaling molecules, thereby attenuating inflammatory responses. TXA treatment significantly reversed these protective effects.

CONCLUSION

Ednrb functions as a key mediator in TXA-induced PTOA progression. The binding of TXA to ETB activates the relaxin and ET-1/ETB pathways, thereby promoting cartilage degradation and inflammation. Targeting Ednrb may represent a promising therapeutic strategy for preventing TXA-associated PTOA.