The reason why inflammation homes to joints in rheumatic diseases is a long-standing mystery. We discovered that an aberrant response to mechanical loading plays a crucial role in joint inflammation. In search of novel drivers of this mechano-inflammation we identified the transcription factor BHLHE40. We will investigate its functional role on connective tissue cells in joints and determine what other arthritis promoting genes it controls. Whether responses to mechanical stress are influenced by genetic risk factors associated with arthritic diseases will also be examined. Thus, we unravel the molecular basis driving mechano-inflammation in joints and assess why this occurs in some individuals more so than others.