Local delivery of OSK factors enables partial cellular reprogramming to mitigate osteoarthritis and cartilage fibrosis

Osteoarthritis (OA) is a prevalent joint disease with a complex etiology, involving epigenetic alterations. Recent studies have suggested the potential of Oct4, Sox2 and Klf4 (OSK) in rejuvenating adult cells and facilitating tissue repair, but their specific role in OA pathophysiology and treatment remains unclear. Here we employed an adeno-associated virus (AAV) vector to achieve ectopic expression of OSK (AAV-OSK). Chondrocytes expressing OSK retained chondrocyte-specific markers with no increase in stemness-associated genes. AAV-OSK significantly preserved chondrocyte vitality in an inflammatory environment and counteracted the upregulation of osteogenic genes during OG differentiation. In OA murine models, AAV-OSK administration led to a notable improvement in cartilage integrity, a reduction in subchondral bone thickening and promoted the hyalinization of fibrocartilage. Furthermore, chondrocyte senescence and DNA methyltransferase expression were markedly diminished in the AAV-OSK group. Tet methylcytosine dioxygenase 2 was identified as a pivotal factor underlying the benefits of OSK-driven cartilage regeneration. Collectively, our study underscores that OSK expression within the knee joint modulates epigenetic alterations, mitigating OA progression and cartilage fibrosis through partial reprogramming, highlighting its therapeutic promise for comprehensive OA intervention.