Fibronectin Peptide FNIII14 Enhances Progressive Cartilage Degeneration in Osteoarthritis by Inducing Chondrocyte...

Osteoarthritis (OA) is highly prevalent worldwide. Fibronectin (FN) has been associated with OA pathology; however, its role remains unexplored. In this study, we hypothesized that FNIII14 induces chondrocyte apoptosis by inactivating β1 integrin and aimed to clarify the role of FNIII14 in OA pathology. Immunohistochemistry, immunofluorescence, flow cytometry, a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, real-time quantitative polymerase chain reaction, and Western blotting were performed using cartilage obtained from patients who underwent total knee arthroplasty. In a mouse model, FNIII14 or phosphate-buffered saline was administered to the knees, and cartilage degeneration and synovitis were evaluated using the Mankin and Synovitis scores, respectively. Statistical significance was determined using the Mann-Whitney U or Kruskal-Wallis test (p < 0.05). FNIII14 was detected in highly degenerated OA cartilage, with decreased β1 integrin activity, suppressed cell proliferation, and induced apoptosis in chondrocytes. FNIII14 decreased the gene expression of cartilage-specific markers and anabolic factors and increased inflammatory cytokine gene expression and phosphorylation of extracellular signal-regulated protein kinase-1/2. FNIII14 induced cartilage degeneration in mouse knees with almost no synovitis. Regulation of FNIII14 production and action may play an important role in suppressing cartilage degeneration in human OA.