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

Area of Science:

• Biomedical Engineering
• Regenerative Medicine
• Epigenetics

Background:

• Osteoarthritis (OA) is a degenerative joint disease with complex causes, including epigenetic changes.
• Oct4, Sox2, and Klf4 (OSK) factors have potential in cell rejuvenation and tissue repair, but their role in OA is not well understood.

Purpose of the Study:

• To investigate the therapeutic potential of ectopic Oct4, Sox2, and Klf4 (OSK) expression using an adeno-associated virus (AAV) vector for osteoarthritis treatment.
• To elucidate the underlying epigenetic mechanisms of OSK-mediated cartilage regeneration in OA.

Main Methods:

• Adeno-associated virus (AAV) vector delivery for ectopic OSK expression in chondrocytes.
• In vitro assessment of chondrocyte markers, stemness, and vitality under inflammatory conditions.
• In vivo studies using OA murine models to evaluate cartilage integrity, bone changes, and fibrosis.
• Analysis of chondrocyte senescence, DNA methyltransferase, and Tet methylcytosine dioxygenase 2 expression.

Main Results:

• AAV-mediated OSK expression preserved chondrocyte phenotype and vitality, counteracting osteogenic gene upregulation.
• In OA models, AAV-OSK improved cartilage structure, reduced subchondral bone thickening, and decreased fibrocartilage formation.
• OSK therapy significantly reduced chondrocyte senescence and DNA methyltransferase expression, with Tet methylcytosine dioxygenase 2 identified as a key mediator.

Conclusions:

• OSK expression in the knee joint modulates epigenetic alterations, mitigating OA progression and cartilage fibrosis via partial reprogramming.
• This study highlights the therapeutic potential of OSK for comprehensive osteoarthritis intervention, emphasizing its role in cartilage regeneration.