Pigmented villonodular synovitis (PVNS) is an idiopathic proliferative synovial process composed of two predominant cell types: mononuclear histiocytic cells and giant cells. This lesion can be locally invasive and can result in bone cyst formation and late cartilage and bone loss. Because metalloproteinases have been implicated in the joint destruction occurring in inflammatory arthritis and in the ability of certain tumors to invade adjacent tissues, their presence in PVNS was determined. Synovial tissue samples were collected at surgical synovectomy from the knees of 10 patients with a prior histological diagnosis of PVNS. Pigmented villonodular synovitis synovium was examined for the presence of the metalloproteinases collagenase and stromelysin. Messenger RNA (mRNA) for collagenase and stromelysin was present in all patient samples, although in varying amounts. In situ hybridization studies on synovial tissue sections identified synovial lining cells as the predominant cells expressing these metalloproteinases. Occasional infiltrating mononuclear histiocytic cells also were producing metalloproteinase mRNA. Giant cells did not express mRNA for the metalloproteinases collagenase and stromelysin. These results suggest that collagenase and stromelysin may be among the mediators of cartilage and bone loss that can occur in PVNS.