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Knee osteoarthritis (KOA) is a common and severe disease characterized by articular cartilage degeneration, subchondral bone remodeling and inflammation. The purpose of this study was to investigate the therapeutic effects of high fibular osteotomy (HFO) in a KOA rabbit model and to examine the molecular mechanisms involved in medial compartment KOA protective effects. Our data showed that HFO delayed the progression of articular cartilage damage and suppressed subchondral bone remodeling in destabilization of the medial meniscus (DMM)-induced KOA model. HFO also decreased MMP-1, MMP-3, MMP-13 and ADAMTS-5 expression, and increased Col2 and aggrecan expression. In parallel, HFO attenuated the expression of IL-1β, IL-6 and TNF-α. Furthermore, HFO suppressed DMM-mediated NFκB activation, which suggested that the molecular mechanism underlying the protective effect of HFO in medial compartment KOA may be related to the NFκB signaling pathway. Collectively, our data indicated that HFO may be a therapeutic approach to treating medial compartment KOA. [ABSTRACT FROM AUTHOR]