Identification of anterior cruciate ligament fibroblasts and their contribution to knee osteoarthritis progression using single-cell analyses.

• We have revealed a new type of fibroblast cell (IAFs) in ACL and its regulatory pathway in KOA. • Micro-CT analysis found that increased expression of BMP2 and RUNX2 in ACL was significantly associated with KOA. • IAFs activate the EREG-EGFR signaling axis by upregulating the expression of SOX5, thereby increasing the inflammatory and osteogenic effects in chondrocytes. The mechanical properties of the anterior cruciate ligament (ACL) in the knee have been highlighted, but its role in the regulation of the joint microenvironment remains unclear, especially in the progression of Knee Osteoarthritis (KOA). Here, single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) data were integrated to reveal the transcriptional and epigenomic landscape of ACL in normal and OA states. We identified a novel subpopulation of fibroblasts in ACL, which provides new insights into the role of the ACL in knee homeostasis and disease. Degeneration of the ACL during OA mechanically alters the knee joint homeostasis and influences the microenvironment by regulating inflammatory- and osteogenic-related factors, thereby contributing to the progression of KOA. Additionally, the specific mechanism by which these Inflammation-associated Fibroblasts (IAFs) regulate KOA progression was uncovered, providing new foundation for the development of targeted treatments for KOA. [ABSTRACT FROM AUTHOR]