| The pathogenesis of osteoarthritis (OA) in both humans and animals is poorly understood. Histological assessment of tissue samples from joints is the most accurate way to diagnose OA severity. Unfortunately, current histological assessment grading schemes, such as the Mankin Histological-Histochemical Grading System (HHGS), are subject to observer variability and are unable to accurately distinguish varying levels of disease severity. The goals of this project were to: (1) develop a novel histological grading scheme to assess OA lesions in mice, (2) apply this scheme to several studies in which OA severity is expected to be influenced by treatment, and (3) compare the reliability and validity of this newly developed scheme to the widely used Mankin HHGS.;Histological sections from the knee (stifle) joints from 5 studies (n=158 joints), including 2 studies using a surgically induced model and 3 studies of naturally occurring disease, were globally examined for changes associated with OA. Changes that were consistent were evaluated using histomorphometry or assigned a grade based on severity. The final scheme that was developed included 13 quantitative and 2 semi-quantitative parameters that evaluated changes in articular cartilage, chondrocytes, subchondral & periarticular bone, and meniscus. Principal Components Analysis combined these 15 parameters into 5 factors that globally evaluated changes in articular cartilage integrity, chondrocyte viability, subchondral bone, periarticular osteophytes, and menisci. This newly developed scheme was then applied to five studies of murine OA, and comparisons among intervention groups in the 15 parameters and 5 factors were evaluated. In addition, the original Mankin HHGS was applied to these same sections. The newly developed scheme identified numerous changes in several tissues in both surgically induced and naturally occurring disease and was able to characterize several changes associated with OA severity in the mouse. While the Mankin HHGS was able to identify significant differences in the surgically induced models, it overlooked changes associated with naturally occurring disease. Finally, a direct comparison between the two schemes revealed that the newly developed scheme was more reliable than the Mankin HHGS, and was also able to correctly distinguish the severities of OA as well as the Mankin HHGS. |
