Although Hif-2α is a master regulator of catabolic factor expression in osteoarthritis development， Hif-2α inhibitors remain undeveloped. The aim of this study was to determine whether Cirsium japonicum var. maackii (CJM) extract and one of its constituents， apigenin， could attenuate the Hif-2α-induced cartilage destruction implicated in osteoarthritis progression. In vitro and in vivo studies demonstrated that CJM reduced the IL-1β-， IL-6， IL-17- and TNF-α-induced up-regulation of MMP3， MMP13， ADAMTS4， ADAMTS5 and COX-2 and blocked osteoarthritis development in a destabilization of the medial meniscus mouse model. Activation of Hif-2α， which directly up-regulates MMP3， MMP13， ADAMTS4， IL-6 and COX-2 expression， is inhibited by CJM extract. Although cirsimarin， cirsimaritin and apigenin are components of CJM and can reduce inflammation， only apigenin effectively reduced Hif-2α expression and inhibited Hif-2α-induced MMP3， MMP13， ADAMTS4， IL-6 and COX-2 expression in articular chondrocytes. IL-1β induction of JNK phosphorylation and IκB degradation， representing a critical pathway for Hif-2α expression， was completely blocked by apigenin in a concentration-dependent manner. Collectively， these effects indicate that CJM and one of its most potent constituents， apigenin， can lead to the development of therapeutic agents for blocking osteoarthritis development as novel Hif-2α inhibitors.