A collaboration between CytoSolve, Inc. and the Division of Orthopedics, Arthritis Program (UHN), a multi-scale molecular systems architecture has been created to provide a comprehensive and integrative molecular systems understanding of human knee osteoarthritis (OA). The architecture is constructed through a supervised bioinformatics process beginning with nearly 20,000 scientific papers curated to a refined set of 5,243 papers from which molecular interactions are extracted. The systems architecture is accessed through an easy-to-use interface to traverse the complexity of knee OA systems biology from tissue to cell to an ensemble of molecular interactions whereby one may discover the particular paper from which an interaction is derived. The systems architecture maintains its currency by enabling the research community to provide feedback that can be reviewed, refereed and incorporated. The architecture provides a framework for developing new educational tools as well as to support research that aims to investigate disease mechanisms, and identify potential therapeutic targets for the treatment of knee OA.