Matrix metalloproteinases (MMPs) in the synovial fluid are responsible for collagen breakdown during physiologic cartilage turnover and the pathologic destruction of the cartilage. We measured the levels of MMPs, specific tissue inhibitors of metalloproteinases (TIMPs), and interleukin-6 (IL-6) in synovial fluid from the knees of 36 patients with cartilage lesions subdivided according to severity based on arthroscopic findings. Lesions were classified as mild (group 1, edema with no disruption of the surface), moderate (group 2, open lesions without exposure of subchondral bone), or severe (group 3, exposure of subchondral bone). Zymography (gel electrophoresis in the presence of hydrolizable substrates) showed a 60-kd band in all samples. A second band (94-kd) was found exclusively in specimens from groups 2 and 3, and a third band (110-kd) was present only in group 3. Concentrations of 2 of the most important modulators of MMP activity, TIMP-1 and IL-6, were measured. TIMP-1 levels did not vary significantly with the severity of cartilage damage. Linear regression analysis revealed a significant positive correlation between TIMP-1 and IL-6 in groups 1 and 2. These data indicate that the severity of the cartilage damage corresponds with MMP activity. The correlation between IL-6 and TIMP-1 in groups with mild and moderate damage suggests a regulating mechanism that is absent in severe lesions.