Increased Rab1a accelerates osteoarthritis by inhibiting autophagy via activation of the mTORC1-S6K pathway

Cartilage degradation is a critical alteration in the progression of osteoarthritis (OA) due to the disorder of chondrocyte metabolic homeostasis. Autophagy plays an important role in maintaining intracellular homeostasis. Recent investigations have increasingly underscored the importance of autophagy in modulating the pathological mechanisms underlying OA. Ras-related protein Rab-1a (Rab1a) has been illustrated to regulate autophagy in many diseases but not in OA.

This study aims to elucidate whether Rab1a could regulate the development of OA through modulation of chondrocyte autophagy and apoptosis.

Proteomic sequencing, Western blotting, and immunohistochemistry were applied to detect the expression level of Rab1a in vitro and in vivo. Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were rigorously identified. The effects of Rab1a and the interaction between Rab1a, mTORC1, autophagy and apoptosis were explored by qPCR, Western blotting, and immunofluorescence. An experimental mouse OA model was also performed to confirm the role of Rab1a in OA pathogenesis in vivo. Histological analysis was employed to demonstrate cartilage damage.

Rab1a expression was significantly upregulated in inflamed chondrocytes and knee OA cartilage. Inhibition of Rab1a partially attenuated the degradation of the extracellular matrix and cell apoptosis both in vitro and in vivo, whereas overexpression of Rab1a intensified cartilage matrix degradation and cellular apoptosis. Additionally, elevated Rab1a levels were observed to suppress autophagy and activate the mTORC1-S6K signaling pathway, thereby aggravating OA pathogenesis.

The augmentation of Rab1a expression impairs autophagy and promotes apoptosis through the activation of the mTORC1-S6K signaling pathway, further exacerbating OA pathogenesis. This finding suggests that Rab1a serves as a promising and innovative therapeutic target for the prevention and treatment of OA.