Osteoarthritis (OA) has been one of the most prevalent joint disorders which cause pain, impair mobility of patients and bring heavy burden to social economics. Unfortunately up to now we still know little about OA. We are not sure what exactly cause OA. The pathogenesis of OA is not clearly understood. Besides, we don’t have effective treatment for OA. When joint degeneration goes to the end-stage, Total Joint Replacement surgery seems to be the only way to relieve pain and restore joint function. Since cartilage degeneration is quite difficult to be stopped or reversed, people are trying to looking into the upstream events which occurred at early stage of Osteoarthritis. Nowadays, early OA changes have drawn attention. It is considered to play an important role in OA initiation and progression and may be the key for OA treatment. However, the exact change at each component of the joint including cartilage, bone and osteochondral junction at early stage of OA is still poorly elucidated. Because it’s quite difficult to obtain information from early staged OA patients, and it’s also difficult to conduct longitudinal observation on human OA patients, we need animal models to obtain knowledge about OA. In this study, we adopted the Dunkin-Hartley (DH) strain guinea pig, which has been widely accepted as aging-related spontaneous OA model. Meanwhile, the pigmented guinea pig was used as OA-resistant control. The aim of this study was to: 1) observe and compare the difference of OA progression between DH and pigmented guinea pigs; 2) characterize the early changes of subchondral bone, cartilage and osteochondral junction in DH strain comparing with pigmented guinea pig; 3) preliminarily investigate the disease-modifying effect of Transforming Growth Factor beta 1 (TGFβ1) receptor inhibitor on OA progression. Significant cartilage degeneration was found in DH strain with cartilage surface disruption, cleft, proteoglycan loss and diffused hypertrophic chondrocytes clustering at age of 12 months. In comparison, cartilage of pigmented guinea pigs remains intact and smooth. At early stage with age from 1 to 3 months, in DH strain, subchondral bone was found to be sclerotic, denser with ultrastructure change, and chondrocytes was found with elevated level of proliferation and apoptosis concurrently, while osteochondral junction was found to be thicker, denser and less porous comparing with pigmented strain. Additionally, TGFβ1 receptor inhibitor was found effective to suppress formation of Bone Marrow Lesion, which is the early sign of OA detected by Magnetic Resonance Imaging. It also preserved the volume of cartilage and subchondral plate against OA degeneration. In conclusion, OA-prone Dunkin-Hartley guinea pigs showed significant cartilage degeneration at age of 12 months. In comparison, pigmented guinea pigs are OA-resistant. At early stage of OA, DH guinea pigs were found with subchondral bone ultrastructure change and chondrocytes hyperproliferation as well as apoptosis. Disease-modifying drugs such as TGFβ1 receptor inhibitor is potentially an option for OA treatment. The finding of this study may contribute to new insight and understanding of early OA pathogenesis and potential development of specific therapeutics strategies. / published_or_final_version / Orthopaedics and Traumatology / Doctoral / Doctor of Philosophy