TGF β-induced cartilage repair is maintained but fibrosis is blocked in the presence of Smad7

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage breakdown, synovial fibrosis, and bone spurs. An imbalance between catabolic and anabolic factors favoring the catabolic side is very likely involved in the pathological features of OA.Currently, many attempts are being made to repair the cartilage that has been damaged in OA. One approach focuses on shifting the metabolic imbalance back by stimulating the anabolic side. Transforming growth factor-β (TGF-β) is one of the anabolic factors involved in cartilage maintenance and appears to be a good candidate for cartilage repair. TGF-β is a stimulator of extracellular matrix production, like collagen type II and proteoglycan (PG), in chondrocytes and it downregulates matrix-degrading enzymes [1]. High amounts of TGF-β are stored in healthy cartilage [2-6], whereas in OA cartilage the expression of TGF-β is reduced [7]. Injection of TGF-β into naive murine knee joints results in an increase in PG content of the articular cartilage [8]. Moreover, in murine experimental rheumatoid arthritis, injection of TGF-β protected cartilage from PG loss [9]. In addition, TGF-β counteracts the anabolic factor interleukin-1 (IL-1), which is a very potent inducer of cartilage degradation [10,11] both in vivo and in vitro [1,12-16]. These data indicate that TGF-β has great potential as a tool for stimulating cartilage repair.To obtain sufficient amounts of TGF-β in the joint for a prolonged period of time, an adenovirus can be used as a vehicle. In vitro, chondrocytes that are transfected with an adenovirus encoding TGF-β responded by elevation of PG and collagen production [17]. We wanted to assess whether adenoviral overexpression of TGF-β in the synovial lining could stimulate repair of damaged cartilage in vivo.Unfortunately, introducing high amounts of TGF-β into a knee joint has adverse effects. Administration of 20 ng TGF-β is already sufficient to result in an increased cellularity of the synovial lin