Osteoarthritis (OA) is a frequently occurring musculoskeletal disorder, leading to joint pain and disability. Although all tissues in the joint can be affected, the focus of this thesis is on changes in bone and cartilage. Evidence from literature suggests that estrogen may have an OA-protective effect. Both cartilage and bone are responsive to estrogen, and therefore the OA-protective effect of estrogen may act via both tissues. In this thesis, we aimed to obtain more insight in the protective effects of estrogen, by investigating the role of estrogen in OA at different levels: The current literature concerning the effects of hormone depletion (by ovariectomy) and estrogen treatment on cartilage in animal models was reviewed in a systematic way. Estrogen receptor knockout mice were studied to investigate the role of estrogen signalling in the osteoarthritic process. Ovariectomy in mice was combined with an osteoarthritis trigger (or a saline injection) and changes in cartilage and bone of both proximal tibia and patella were described. The effects of estrogen on cartilage without interference of surrounding tissues were investigated in a culture study of bovine cartilage explants. In conclusion, the results in this thesis support the idea that OA is a multifactorial disease, in which the contribution of estrogen may be small. However the estrogen-induced changes, together with changes caused by other contributors, can result in osteoarthritis.