When healing turns fibrotic: Exploring molecular mechanisms and therapeutic strategies for knee arthrofibrosis

Knee arthrofibrosis is a serious complication most commonly arising after anterior cruciate ligament reconstruction or total knee arthroplasty, as well as a part of knee osteoarthritis pathology. It is characterized by excessive extracellular matrix deposition, joint stiffness and loss of joint mobility. Fibrosis has been extensively studied in organs such as the liver, lung, and heart, but knee joint fibrosis remains largely neglected, with no approved therapies or ongoing clinical trials targeting its underlying mechanisms. This review presents a comprehensive overview of the cellular and molecular pathways driving pathological fibrosis. We detail the activation and phenotypic diversity of macrophages and fibroblasts, highlighting how dysregulated interactions between these cell types establish self-perpetuating fibrotic loops. The most important mediators and signalling pathways are discussed, as well as the role of enzymes lysyl oxidase, transglutaminase-2 and matrix metalloproteinases in the formation of the fibrotic tissue. An overview of the latest drug candidates under clinical investigation in the last 5 years for other fibrotic conditions was provided, while potential directions for druggable targets specifically related to the knee joint arthrofibrosis were proposed, such as hypoxia inducible factor 1-alpha, nuclear protein 1, Hippo signalling pathway, and Wnt signalling. Particular emphasis is given to some innovative local (intra-articular) drug delivery systems based on micro- and nanoparticles, hydrogels, and extracellular vesicles. Advancing our understanding of knee-specific fibrotic mechanisms is critical to developing effective, mechanism-driven treatments for knee arthrofibrosis.