Losartan alleviated synovitis in patients with metabolic osteoarthritis by down-regulating AT1R to inhibit TGF-β signaling.

Previous studies have shown that losartan can alleviate the progression of osteoarthritis (OA). This study aimed to further explore the therapeutic effect and mechanism of losartan on metabolic OA. In obese OA patients, we found that patients with BMI > 28 had higher synovitis score and higher expression of inflammatory factors compared with BMI < 23, and angiotensin receptor type 1(AT1R) expression were also significantly increased. In high-fat diet (HFD) rat model, the HFD group had higher synovitis scores and OARSI scores, significantly increased expression of inflammatory factors in synovium (SM), significantly decreased matrix synthesis genes and increased degradation genes in cartilage. However, they were significantly alleviated in the HFD + losartan group. In the HFD group, AT1R expression was significantly increased in SM, but was significantly decreased after losartan administration. In vitro co-culture experiments showed that sodium palmitate (PA) could concentration-dependently promote the production of inflammatory factors in fibroblast-like synoviocytes (FLS) and the reduction of extracellular matrix in chondrocytes, while losartan could reverse these effects. In addition, PA could promote of AT1R/TGF-β/Smad2/3 pathway in FLS, which was reversed by either AT1R siRNA or losartan. In summary, we demonstrated that losartan alleviates synovial inflammation in patients with metabolic OA by down-regulating AT1R to inhibit TGF-β/Smad2/3 signaling pathway in SM.