Zone of Calcified Cartilage – a Natural Boarder in the Osteochondral Unit to Control Diffusion of Molecules between Articular Cartilage and Subchondral Bone

• Applicant: Dr. Andrea Schwab
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 491667286

Osteoarthritis (OA) is the commonest joint disease worldwide with more than 20% of the German society suffering from this painful and disabling disease. Physiological and pathological changes during OA include the degeneration and erosion of cartilage tissue up to the exposure of the underlying bone. To intervene the progression of this disease, there is urgent need to better understand the mechanisms at molecular, cell and tissue level of the osteochondral unit, especially the zone of calcified layer (ZCC). The ZCC is connecting the deep zone of non-calcified articular cartilage to the subchondral bone. However, little is known about the role of the ZCC in cartilage homeostasis, the steady state condition of healthy tissue.I hypothesize that the ZCC serves as a natural border that controls the diffusion of molecules between cartilage and bone tissue and regulates cell-cell communication. This permeability is altered upon onset of OA leading to changes in cytokines and morphogens in the extracellular matrix inducing phenotypic changes in chondrocytes. I will approach this topic from two perspectives: the macroscopic tissue-level and the microscopic cellular-level. The first objective covers the quantification of molecules that can pass through human ZCC ex vivo from bone to cartilage and vice versa using advanced 3D imaging techniques and spectrophotometry. The size of molecules passing the ZCC and their location in this thin tissue layer will be correlated to the structural changes in the osteochondral tissue of OA patients. The second objective focuses on the identification of gene expression patterns specific for hypertrophic chondrocytes residing in the calcified cartilage using next generation sequencing technique. This library will be used to compare how specific molecules (morphogens and growth factors) can stimulate chondrocytes isolated from non-calcified cartilage of the deep zone to undergo differentiation towards hypertrophic chondrocytes in vitro and how close these changes match with the phenotype of hypertrophic OA chondrocytes.In close collaboration with the host and guest research groups, I will generate new knowledge and insights on the regulatory role of the ZCC in cartilage homeostasis and OA progression. The characterization of diffusion properties through the ZCC in human explants, together with the response of deep zone chondrocyte to environmental factors in vitro will provide a unique approach to deeper understand the mechanism related to hypertrophic differentiation during OA. This knowledge will result in novel approaches to impede or delay OA progression and cartilage degeneration.

• DFG Programme: WBP Position