Osteoarthritis (OA) is the most common joint disease affecting >500million people worldwide (>2.5 million Australians) and the leading cause of chronic pain and disability. With no cure or currently approved disease modifying therapies, and increases in key risk factors such as ageing, overweight/obesity and joint injury, this number is conservatively estimated to rise by 50% over the next 10 years. Developing new and effective therapies for OA depends on better understanding disease pathophysiology. While long considered the consequence of aberrant joint mechanics, particularly in injury-induced post-traumatic OA, new data is implicating a key role for inflammation in OA pathogenesis. I will the latest data from our studies using animal models of joint-injury and OA demonstrating a key role for both innate and adaptive immune responses in OA onset and progression. In addition to the direct musculoskeletal consequences, individuals with OA have ~2-fold increased risk of cardiovascular disease (CVD). The prevailing paradigm is that the OA:CVD association is driven by shared risk-factors and OA reducing physical activity and increasing NSAID use. I will share our data from both animal models and human patient with joint-injury that supports a new disease paradigm where bioactive factors released from diseased joints directly induce cardio-vascular cell pathology thereby increasing CVD risk: “bad knees can cause broken hearts”.