Oxytocin‐loaded hydrogel promotes cartilage regeneration and regulates microenvironment

Abstract Osteoarthritis (OA) is a common orthopedic condition, and traditional treatment methods often fail to regenerate cartilage effectively. Oxytocin (OXT) is a neuropeptide that plays a crucial role in the skeletal system. Hyaluronic acid (HAMA) hydrogel has emerged as a key carrier for cartilage repair due to its excellent biocompatibility and biodegradability. Combining OXT with HAMA hydrogel and implanting it at the site of cartilage defects can effectively promote cartilage regeneration. Cartilage damage often results in an altered microenvironment, characterized by macrophage polarization and high levels of reactive oxygen species (ROS). Oxidative stress can stimulate macrophages to produce more pro-inflammatory factors. OXT can inhibit the secretion of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β by interacting with the STAT3/NF-κB signaling pathway, as well as the PI3K/Akt and MAPK pathways, thereby inducing the polarization of macrophages from the M1 phenotype to the M2 phenotype and alleviating the inflammatory response. OXT can also enhance the expression of NRF and HO-1, which helps eliminate reactive oxygen species and suppress the expression of pro-inflammatory factors. Regulating the microenvironment of cartilage damage is beneficial for cartilage protection and repair. OXT activates the CFOS/AP-1 and STAT1/JAK2 pathways, which together act on MMP2 and MMP9 to alleviate cartilage degeneration. The STAT1/JAK2 pathway can further increase the expression of Col2, thereby protecting chondrocytes. Additionally, OXT can directly boost the protein levels of SOX9 and COMP, promoting chondrocyte proliferation and cartilage protection, ultimately achieving the therapeutic goal for arthritis. This study explores the potential of HAMA hydrogel as a delivery system for OXT and analyzes their impact on cartilage regeneration and anti-inflammatory properties. This research provides a novel strategy for the treatment of cartilage injuries.