Targeting a key pro-fibrotic factor S100A4 in cartilage to alleviate osteoarthritis progression and pain

Osteoarthritis (OA) is the most prevalent degenerative joint disease marked by cartilage degeneration, synovial inflammation and pain, which seriously affects life quality of patients. However, due to unclear pathological mechanisms, there is still lack of specific targets at the molecular level for OA treatment. Since OA-related cartilage displays pathological features of fibrosis, such as increased secretion of collagen I (COL I) but decreased secretion of collagen II (COL II), and cartilage fibrosis is usually defined as a final-stage of OA, we hypothesized that fibrosis related factors could promote OA progression. By combining public databases with pathological analysis of clinical OA immunohistochemistry samples, we found that a key pro-fibrotic factor, S100A4, also named fibroblast specific protein-1 (FSP-1), was overexpressed by OA chondrocytes and positively related with OA progression. To investigate if S100A4 can be a therapeutic target of OA, we designed cartilage-targeting lipid nanoparticles (CT-LNP) loading S100A4 siRNA (CT-LNP-siA4) to silence the S100A4 gene in OA chondrocytes. In both mouse and rat OA models, CT-LNP-siA4 could significantly downregulate the expression of S100A4 and OA phenotype-related molecules, such as COL I, MMP-13, and IL-6, inhibiting OA progression and chronic pain. This study validated S100A4 as a potential molecular target and proved that the corresponding LNP drug formulation was effective for the OA treatment at various animal models.