Osteoarthritis (OA) is a major cause of morbidity and disability in the elderly and imposes significant economic burden on society. It has been recognized for over a decade that OA progression is intimately coupled with specific, complex molecular transcriptional programs and signaling pathways. Understanding the regulation of these pathways in OA is required to develop new strategies for prevention, detection, and treatment of the disease. In the first part of my talk, I will describe the molecular and structural changes seen in OA that includes not only the remodelling of articular cartilage and underlying subchondral bone but also the synovium inflammation and osteochondral junction to define the normal and diseased tissues. I will then discuss how the altered subchondral bone and articular cartilage communications have been implicated in the pathogenesis of OA and the mechanisms involved during this altered bi-directional communication. In the last part of my talk, I will discuss the influence of Metabolic syndrome and obesity on OA, with a specific focus on the mechanisms through which these systemic factors influence inflammatory processes and chondrocyte degenerative changes.