Objective: Osteoarthritis (OA) is a serious disease of the entire joint, characterized by degeneration of articular cartilage, subchondral bone changes, osteophyte formation and synovial hyperplasia. Currently, there are no pharmaceutical treatments to slow disease progression, resulting in greatly reduced quality of life for patients and the need for joint replacement surgeries in many cases. The lack of available treatments for OA is partially due to our incomplete understanding of the molecular mechanisms promoting disease initiation and progression. Here we identify the nuclear receptor PPARdelta as a promoter of cartilage degeneration in a mouse model of post-traumatic OA.Methods: Mouse chondrocytes and knee explants were treated with a pharmacological agonist of PPARdelta (GW501516) to evaluate changes in gene expression, histology and matrix glycosaminoglycan breakdown. In vivo, PPARdelta was specifically deleted in the cartilage of mice. Mutant and control mice were compared after destabilization of medial meniscus (DMM) surgery by histopathological scoring (OARSI) and immunohistochemistry.Results: In vitro, PPARdelta activation by GW501516 results in increased expression of several proteases in chondrocytes as well as aggrecan degradation and glycosaminoglycan release in knee joint explants. In vivo, cartilage specific Ppard knockout mice do not display any abnormalities of skeletal development, but show marked protection in the DMM model of post-traumatic OA (compared to control littermates). OARSI scoring and immunohistochemistry confirm strong protection of mutant mice from DMM-induced cartilage degeneration.Conclusion: These data demonstrate a catabolic role of endogenous PPARdelta in post-traumatic OA and suggest that pharmacological inhibition of PPARdelta is a promising therapeutic strategy. © 2014 American College of Rheumatology.