†shared last authorship. One Sentence Summary:We report a correlation between articular cartilage surface nanoscale stiffness and chondrocyte spatial organization; using this correlation enables early pathology detection by currently available clinical optical methods. Abstract:Osteoarthritis (OA) is a degenerative joint disease and the leading cause of global disability.Clinical trials to date have been unable to pinpoint early and potentially reversible disease states with current clinical technology and hence disease-modifying OA drug candidates cannot be tested early in the disease. To overcome this obstacle, we correlate articular cartilage stiffness changes and cellular spatial organization. The former is a well-understood and functionally relevant OA pathology, while the latter allows discriminating between healthy vs early OA, based on distinct cellular spatial patterns. We demonstrated that an extensive loss of atomic force microscopydetected stiffness can be seen in cartilage tissues with spatial patterns exhibiting the earliest identifiable OA. In addition, the translation of commercially available clinically usable probebased confocal laser-endomicroscopy allows us to detect these early OA spatial patterns. This study resolves a major clinical trial obstacle by presenting the proof-of-concept that early OA pathology can be detected by already available clinical technology.