Ultrasound-targeted simvastatin-loaded microbubble destruction promotes OA cartilage repair by modulating the cholesterol efflux pathway mediated by PPAR gamma in rabbits

Aims To evaluate the effect of ultrasound-targeted simvastatin-loaded microbubble destruction (UTMDSV) for alleviation of the progression of osteoarthritis (OA) in rabbits through modulation of the peroxisome proliferator-activated receptor (PPAR gamma). Methods In vitro, OA chondrocytes were treated with ultrasound (US), US-targeted microbubble destruction (UTMD), simvastatin (SV), and UTMDSV on alternate days for four weeks. Chondrocytes were also treated with PPAR gamma inhibitor, PPAR gamma inhibitor+ UTMDSV, and UTMDSV. The cholesterol efflux rate and triglyceride levels were measured using an assay kit and oil red O staining, respectively. In vivo, the OA rabbits were treated with a single intra-articular injection of UTMD, SV, and UTMDSV every seven days for four weeks. Cartilage histopathology was assessed by safranin- O staining and the Mankin score. Total cholesterol (TC) and high-density lipoprotein-cholesterol (HDL-C) in rabbit knee synovial fluid were detected by enzyme-marker assay. Aggrecan, collagen II, and PPAR gamma expression levels were analyzed by Western blotting (WB). Results In vitro, UTMDSV significantly increased the cholesterol efflux rate and aggrecan, collagen II, and PPAR gamma levels in OA chondrocytes; these effects were blocked by the PPAR gamma inhibitor. In vivo, UTMDSV significantly increased aggrecan, collagen II, PPAR gamma, and HDL-C levels, while TC levels and Mankin scores were decreased compared with the UTMD, SV, OA, and control groups. Conclusion UTMDSV promotes cartilage extracellular matrix synthesis by modulating the PPAR gamma-mediat-ed cholesterol efflux pathway in OA rabbits.