Manipulating chondrogenic progenitor cells in osteoarthritis for cartilage repair in humans

• Applicant: Professor Dr. Nicolai Miosge
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2012 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 214325115

Regeneration of diseased hyaline cartilage tissue in osteoarthritis (OA) continues to be a great challenge because degeneration overrides the tissue self-renewal capacity. Recently, we identified multipotent, clonogenic and migratory cells, which are present in the repair tissue of late stages of OA. The chondrogenic potential of these chondrogenic progenitor cells (CPCs) in human OA cartilage tissue is controlled by the counteracting transcription factors runx2 and sox9 (Koelling et al. 2009, Cell Stem Cell). Down-regulation of runx2 enhances sox9 expression and thereby the production of hyaline matrix molecules. Direct manipulation of these essential players is not feasible as a therapeutic approach due to their broad actions. Therefore, we have elucidated co-regulators of runx2 and sox9 -for example, RAB5C, YWHAE, DDX5, LEMD2- that up-regulate sox9 and down-regulate runx2. We aim to overexpress and knock-down (CRISPAR/Cas9) these co-regulators to enhance chondrogenesis in human CPCs. To pave the way for their use in a mouse model, the mouse homologues of these co-regulators will be applied in mouse CPCs from an OA mouse model (BMP2-Gdf5cKO). Co-regulators enhancing sox9 and reducing runx2 in mouse and human CPC will be transfected in mouse CPCs and embedded in a hydrogel implanted in nude mice. This in vivo mouse experiment will elucidate the chondrogenic potential of manipulated CPCs in situ. The results will help to manipulate CPCs towards chondrogenesis in a more fine-tuned way to open new avenues for the cell biological treatment of OA to repair cartilage and postpone total knee replacement.

• DFG Programme: Research Grants