LRP1 Mediates Endocytosis Activity and Is a Potential Therapeutic Target in Osteoarthritis.

Osteoarthritis (OA) is a degenerative disease characterized by cartilage abrasion and pain, affecting millions globally. However, current treatments focus on symptom management rather than modifying disease development. Recent studies have indicated that low-density lipoprotein receptor-related protein 1 (LRP1) is associated with maintaining cartilage homeostasis through its involvement in endocytosis and signaling pathways. LRP1 facilitates the removal of extracellular matrix (ECM)-degrading enzymes, including a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) and matrix metalloproteinases (MMPs), thereby protecting against excessive cartilage breakdown. However, OA cartilage shows increased shedding of LRP1, leading to reduced endocytic capacity and elevated levels of these enzymes, contributing to accelerated ECM breakdown. LRP1 is also involved in key signaling pathways, such as Wnt/β-catenin, transforming growth factor-beta (TGF-β), and nuclear factor-kappa B (NF-κB), which regulate processes like chondrocyte proliferation, apoptosis, differentiation, and autophagy. Dysregulation of these pathways, combined with impaired LRP1-mediated endocytosis, fosters a catabolic environment in osteoarthritic cartilage. Emerging therapies targeting LRP1, such as gene interventions, exosome-based therapies, and small-molecule modulators, show potential in restoring LRP1 function, reducing cartilage degradation, and promoting joint repair. This review emphasizes the significance of LRP1 in the development of OA and explores its potential as a therapeutic target for creating disease-modifying strategies to maintain joint integrity and enhance patient well-being.