Intraarticular Gene Transfer of Thrombospondin-1 Suppresses the Disease Progression of Experimental Osteoarthritis

In osteoarthritis, angiogenesis, which occurs in the osteochondral junction and synovium, may accelerate inflammation and contribute to the severity of the disease. We used anterior cruciate ligament-transection (ACLT) to investigate the therapeutic effect of an angiogenesis inhibitor, thrombospondin-1 (TSP-1), in a rat model of osteoarthritis. Osteoarthritis was induced in Wistar rats in the knee of one hind leg. After ACLT, AdTSP-1 (adenoviral vector encoding mouse TSP-1) was intraarticularly injected into the knee joints. Transgene expression, angiogenesis, and inflammatory responses in the knee joints were examined. They were also assessed morphologically, radiographically, and histologically for manifestations of disease. The levels of TSP-1 peaked on day 3 and were substantially maintained for at least 9 days after AdTSP-1 infection. Adenovirus-mediated gene expression was detected in the synovial membrane and chondrocytes. TSP-1 gene transfer induced transforming growth factor-b (TGF-b) production, but it reduced microvessel density, macrophage infiltration, and interleukin-1b (IL-1b) levels. Gross morphological and histopathological examinations revealed that rats treated with AdTSP-1 had less severe osteoarthritis than controls. In vivo adenovirus-mediated TSP-1 gene transfer significantly reduced microvessel density, inflammation, and suppressed the progression of osteoarthritis. This study provides potential applications of TSP-1 gene delivery for treating osteoarthritis. 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1300-1306, 2010 Osteoarthritis is commonly believed to be a disorder of the cartilage with the associated features of cartilage loss, osteophyte formation, and synovial inflammation. Angiogenesis, the formation of new blood vessels, contributes to each of these features and causes changes in the articular cartilage. 1 The invasion of blood vessels is accompanied by cartilage matrix degradation. 2 Angio- genesis at the osteochondral junction leads to endochon- dral ossification and the formation of osteophytes. 3 Furthermore, vascular growth is also higher in the synovium from patients with than without osteoarthri- tis and is associated with synovitis. 4 Osteochondral angiogenesis facilitates the progression of osteoarthri- tis. 5 Angiogenesis and inflammation interact and mutually affect each other in the osteoarthritic joint. The inflammatory factors transported by newly formed vascular channels may potentate inflammation and further impair the homeostasis of the cartilage, thereby exacerbating osteoarthritis. Moreover, vascular inva- sion contributes to symptoms by facilitating sensory nerve growth into the articular cartilage. 6 By retarding