Overexpression of active TGF-beta-1 in the murine knee joint: evidence for synovial-layer-dependent chondro-osteophyte formation

OBJECTIVE: To investigate the impact of a prolonged and constant active TGF-beta expression by the synovial lining cells on cartilage and ligamentous joint structures in vivo. DESIGN: An adenoviral vector (AdTGF-beta1(223,225)) was used for the overexpression of active TGF-beta1 in knee joints of C57Bl/6 mice. RESULTS: It was found that physiological relevant levels of active TGF-beta1 produced by the synovial lining layer resulted in histopathological changes: hyperplasia of synovium and chondro-osteophyte formation at the so-called chondro-synovial junctions. No histological changes were seen after intra-articular injection of an empty control vector (AdDL70-3) or by overexpression of latent TGF-beta1 (AdTGF-beta1). The predominant site of TGF-beta production in osteoarthritis (OA) and rheumatoid arthritis (RA) is the synovial lining layer. To address the question whether the TGF-beta-induced changes were related to the expression site in the synovial lining, the synovial lining layer was depleted by local treatment with liposomes encapsulating clodronate. Depletion of the lining resulted in a dramatic change of TGF-beta1-induced pathology: markedly reduced chondro-osteophyte formation and increased accumulation of extracellular matrix in the synovium. CONCLUSION: This study shows that overexpression of active TGF-beta1 in the knee joint results in OA-like changes and suggests the synovial lining cells contribute to the chondro-osteophyte formation.