Combined preclinical in vivo and clinical in silico modelling of pathological cartilage loading damage and osteoarthritis

H. Madry, M. Cucchiarini, Saarland University & G. Duda, Charité

Abstract: Although it is clear that specific molecular events and pathological mechanical loading are both associated with the onset of early cartilage degeneration, to date a direct link between them has not been established. This proposal aims to study the pathological and clinical consequences of axial mal-alignment-induced cartilage overloading and its therapeutic redistribution in a preclinical animal model of early osteoarthritis. In a sheep HTO model of varus and valgus alignment, pathological cartilage loading damage and the onset of osteoarthritis following partial medial meniscectomy will be studied at the molecular (VORTKAMP, PAP), cellular, biochemical (PAP, SCHULZE-TANZIL, KNAUS) and microstructural (CHONDROMETRICS, ZACHOW) level in the medial femoro-tibial osteochondral unit and compared with non-osteotomized controls. Biomarkers tested will be similar than in the FELSENBERG clinical trial. Relevant sheep tissue samples (e.g. muscle) will be also provided to clarify pro-algesic and analgesic mechanisms (MACHELSKA). Within this project, our knowledge of the effect of loading on osteoarthritic cartilage degradation over time will be significantly improved. This data will be also used by HEGE, VON KLEIST to compute and by DUDA to analyze and correlate musculoskeletal loading patterns in the sheep hind limb. It therefore provides the basis to connect osteoarthritic degeneration to mechanical tissue strains in overloaded knee compartments. Finally, clinical data from the association between axial mal-alignment, load characteristics, and osteoarthritis (PERKA) will be compared with these preclinical correlations to better tailor therapeutic HTO interventions in patients. This project therefore serves as a pillar to bridge the understanding of developmental determinants of loads, the mechano-sensitive signaling with the tissue imaging and the human situation as assessed in the other collaborative projects.

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