Multidimensional analysis of the mechanisms of early osteoarthritis

• Applicant: Professor Dr. Henning Madry
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517789576

Early osteoarthritis (OA) is a key phase during the disease, affecting not only the articular cartilage, but progressively involving all parts of a joint, among which the synovial membrane, the osteochondral unit and menisci. Recently, a location-dependency of tibiofemoral OA has been identified. This discovery represents a critical paradigm shift, because such topographical patterns may enable a precise numerical assessment of the disease. By analyzing the spatiotemporal changes of OA development at mid-term in a clinically relevant sheep model, we identified a specific topographical pattern of osteochondral changes instructed by a defined meniscal injury, showing that both cartilage and subchondral bone degeneration are initiated from the region adjacent to the damage, inducing alterations of the subarticular spongiosa that precisely indicate disease progression. We validated these findings against human OA, showing a similar pattern of early OA correlating with regions of meniscal loss and an analogous late critical disturbance within the entire osteochondral unit. We also showed that multivariate analyses are capable of explicitly defining associations between such location-dependent parameters and clinical measures of OA. However, a clear mechanistic and quantitative understanding of the spatiotemporal cascade at the very onset of OA remains to be determined. Moreover, how the structural and functional tissue-specific indices interact in early OA with systemic mediators is not well understood mechanistically. Finally, solid scientific in vivo evidence supporting the notion meniscus repair can prevent OA development on a structural and functional level at long-term is practically absent. We here aim in the ovine model (1) to investigate the time-course of the very early tissue-specific structural and functional spatiotemporal trajectories of OA following a traumatic meniscus tear in vivo at high resolution, (2) to decelerate OA progression at long-term by reconstructing a traumatic meniscus tear to restore the disturbed tissue-specific structural and functional spatiotemporal patterns in vivo and (3) to monitor the regulation of systemic mediators (e. g. microRNAs) following a traumatic meniscus tear and its repair to identify their association with tissue-specific indices of OA in vivo. This approach will enable to explicitly define associations between the location-dependent structural and functional parameters with clinically relevant systemic measures of OA that are of high translational value.

• DFG Programme: Research Grants