It is increasingly recognized that the pathogenesis of cartilage degradation in osteoarthritis (OA) is multifactorial and involves the interactions between cartilage and its surrounding tissues. These interactions regulate proinflammatory cytokine-mediated cartilage destruction, contributing to OA progression as well as cartilage repair. This review explores the pathogenesis of OA in the context of the multiple tissue types in the joint and discusses the implications of such complex tissue interaction in the development of anti-inflammatory therapeutics for the treatment of OA.