Mechanoregulated microRNAs in cartilage function and pathophysiology of osteoarthritis

• Applicant: Privatdozentin Dr. Solvig Diederichs, since 1/2023
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277277765

Mechanical joint loading is an essential factor in joint homeostasis but also the most important etiological factor in the development of osteoarthritis (OA). In the first funding period we defined the first mechanosensitive microRNA (miR) panel regulated in engineered human cartilage exposed to anabolic and catabolic loading regimes, proposed integrin and cell adhesion molecules as candidate targets and uncovered a need for adaptation of extracellular matrix (ECM)-cell interaction and replacement of lost proteoglycans in response to loading. We showed that WNT and BMP-activity changed with cartilage ECM content, were highly relevant for GAG-synthesis after loading and, thus, influenced the mechano-competence of the tissue. Overall, parameters typical for OA cartilage like a lower ECM content on the one hand and a hypertrophic phenotype of chondrocytes on the other had negative influences on load-induced changes in proteoglycan-synthesis, demonstrating a reduced mechano-competence of cartilage with OA features. Loading shifted expression away from collagen-binding ITGA11/ITGA10 towards fibronectin-binding ITGA5 and a confirmed link of mechano-miR regulation to mechano-signaling via pERK1/2 puts integrin-derived plus FGFR-dependent ERK1/2 signaling into focus for future work. We propose for the extension period to refine, in cooperation with members of the consortium, the diagnostic utility of the new mechano-miRs for load-bearing cartilage and a potential transmission into synovial fluid and serum levels of OA patients with confirmed overloading history. We plan to deepen our understanding of mechanisms and mechano-miR function by exposing cartilage to pain-sensitizing molecules during loading and by putting three routes of mechanotransduction from ECM to chondrocytes into focus: i) direct force transduction from collagens/fibronectins to ß1-integrins, ii) force-related release of ECM-stored FGF activating FGF-receptor signaling and iii) force-dependent modulation of the pericellular heparan sulfate-bound growth factor reservoir in cartilage by imitating OA-related changes of HS-sulfation in our in vitro OA model. As mechanical signals drive both beneficial responses as well as those that drive disease, knowledge on the most important mechanisms and pathways of mechanosignaling will provide a choice of strategies for diagnosing and treating OA.

• DFG Programme: Research Units
• Subproject of: FOR 2407: Exploring Articular Cartilage and Subchondral Bone Degeneration and Regeneration in Osteoarthritis (ExCarBon)
• Ehemalige Antragstellerin: Professorin Dr. Wiltrud Richter, until 12/2022