Abstract Background: The primary feature of osteoarthritis is cartilage loss. In addition, osteophytes can frequently be observed. Transforming growth factor-β (TGFβ) has been suggested to be associated with protection against cartilage damage and new cartilage formation as seen in osteophytes. Objective: To study TGFβ and TGFβ signalling in experimental osteoarthritis to gain insight into the role of TGFβ in cartilage degradation and osteophyte formation during osteoarthritis progression. Methods: Histological sections of murine knee joints were stained immunohistochemically for TGFβ3 and phosphorylated SMAD-2 (SMAD-2P). Expression patterns were studied in two murine osteoarthritis models, representing spontaneous (STR/ort model) and instability-associated osteoarthritis (collagenase-induced instability model). Results: TGFβ3 and SMAD-2P staining was increasingly reduced in cartilage during osteoarthritis progression in both models. Severely damaged cartilage was negative for TGFβ3. In contrast, bone morphogenetic protein-2 (BMP-2) expression was increased. In chondrocyte clusters, preceding osteophyte formation, TGFβ3 and SMAD-2P were strongly expressed. In early osteophytes, TGFβ3 was found in the outer fibrous layer, in the peripheral chondroblasts and in the core. Late osteophytes expressed TGFβ3 only in the fibrous layer. SMAD-2P was found throughout the osteophyte at all stages. In the late-stage osteophytes, BMP-2 was strongly expressed. Conclusion: Data show that lack of TGFβ3 is associated with cartilage damage, suggesting loss of the protective effect of TGFβ3 during osteoarthritis progression. Additionally, our results indicate that TGFβ3 is involved in early osteophyte development, whereas BMP might be involved in late osteophyte development.