A therapeutic-grade purified exosome system alleviates osteoarthritis by regulating autophagy through the BCL2-Beclin1 axis.

BACKGROUND: Osteoarthritis is a common and progressive degenerative joint disorder marked by cartilage degradation, subchondral bone remodeling, and chondrocyte apoptosis. Autophagy, a tightly regulated intracellular degradation process, is essential for maintaining chondrocyte homeostasis. Dysregulated autophagy can contribute to cartilage degeneration by disrupting the balance between cellular survival and death. The B-cell lymphoma 2 (BCL2) protein plays a dual role by inhibiting autophagy via its interaction with Beclin-1 while simultaneously suppressing apoptosis. This study aimed to investigate whether a therapeutic-grade purified exosome system derived from human plasma can modulate autophagy through regulation of BCL2 signaling, reduce chondrocyte apoptosis, and prevent osteoarthritis progression. RESULTS: In vitro experiments demonstrated that exosome treatment increased autophagic activity and reduced apoptosis in both immortalized and osteoarthritic human chondrocytes. Mechanistic analysis revealed that exosomes downregulated BCL2 expression, disrupted the BCL2-Beclin-1 complex, and enhanced the expression of autophagy-related proteins LC3 and Beclin-1. Overexpression of BCL2 reversed these effects and led to impaired autophagic flux and elevated apoptosis, particularly in osteoarthritic chondrocytes. In a rat model of surgically induced osteoarthritis, intra-articular injection of the exosome product mixed with hyaluronic acid improved gait parameters, reduced mechanical pain sensitivity, and preserved cartilage architecture and subchondral bone structure. Histological and molecular analyses confirmed reduced chondrocyte apoptosis and elevated autophagic activity in exosome-treated joints, along with decreased BCL2 expression and complex formation with Beclin-1. CONCLUSIONS: This study demonstrates that a therapeutic-grade exosome formulation can alleviate osteoarthritis by restoring the balance between autophagy and apoptosis through modulation of the BCL2-Beclin-1 signaling axis. These findings highlight the potential of exosome-based nanotherapeutics as a novel disease-modifying treatment strategy for degenerative joint disorders.