Ultrasound therapy inhibits knee osteoarthritis progression in rabbits by activating the PPARs pathway: a pilot study

Ultrasound (US) is effective in knee osteoarthritis (KOA), but its therapeutic mechanism is unclear, particularly the interaction between US and peroxisome proliferator-activated receptors (PPARs). This study aims to elucidate the therapeutic mechanism of US through PPARs signaling. A surgically induced KOA rabbit model evaluated the therapeutic effects of Sham US, US, Fenofibrate (PPAR-α agonist), and Rosiglitazone (PPAR-γ agonist) via MRI. Cartilage and synovium tissues were collected for immunohistochemistry, RT-PCR, and western blotting. Synovial fluid inflammatory factors were analyzed. We also developed an <i>in vitro</i> cultured KOA chondrocyte model to investigate the effects of US therapy on PPARs-related signaling pathways and extracellular matrix cytokines. The mechanism by which US therapy inhibits KOA was studied using GW6471 (PPAR-α antagonist) and Mifobate (PPAR-γ antagonist). MRI revealed that US therapy slowed cartilage thinning and improved cartilage structure in the KOA model. Concurrently, US therapy effectively reduced chondrocyte damage and degradation <i>via</i> modulating mRNA and protein levels of PPARs-related signaling pathways in both cartilage and synovial tissues. Additionally, US therapy suppressed synovial inflammation by downregulating pro-inflammatory cytokines such as interleukin-6, interleukin-1β, and tumor necrosis factor-α, while promoting extracellular matrix homeostasis through the upregulation of aquaporin 7 and Collagen II levels <i>in vivo</i> and <i>in vitro</i>. By maintaining cartilage-chondrocyte equilibrium, US therapy prevented GW6471 or Mifobate’s KOA-promoting impact. Our results show that US therapy could arrest the progression of KOA by reducing synovial inflammation, delaying cartilage degradation, and decreasing extracellular matrix degradation <i>via</i> PPARs-related signaling pathways.