Molecular role of PIEZO1 in endochondral ossification

• Applicants: Professorin Dr. Anita Ignatius; Professor Dr. Thorsten Schinke, Ph.D.
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467458614

Skeletal development, growth and remodeling are highly complex processes involving many different cell types with unique functions. The majority of the axial and appendicular skeleton develops by endochondral ossification, a process depending on chondrocytes, which produce a cartilage intermediate that is subsequently replaced by bone. We have previously identified a key role of the mechanically activated ion channel PIEZO1 in both, skeletal remodeling and endochondral ossification. Whereas the first function of PIEZO1 depends on its expression in bone-embedded osteocytes, its role in endochondral ossification is mediated by PIEZO1 expression in growth plate chondrocytes. More specifically, our collective analyses of conditional mouse models with PIEZO1 deficiency in different skeletal cell types has demonstrated that chondrocyte-specific PIEZO1 inactivation strongly impairs postnatal trabecular bone formation. Moreover, molecular experiments with cultured bone cells suggested that PIEZO1 specifically controls the chondrocyte-to-osteoblast transdifferentation process. The primary goal of this project is to fully uncover the molecular role of PIEZO1 in chondrocytes, also taking advantage of additional mouse models allowing inducible PIEZO1 inactivation and lineage tracing. We will also combine the chondrocyte-specific PIEZO1 inactivation with other genetic modifications to specify the role of potential downstream mediators. Since the process of endochondral ossification is also recapitulated during fracture healing, we want to take advantage of our existing expertise in analyzing this process in a controlled osteotomy model. Finally, cell culture experiments will be performed to link the in vivo findings to impaired mechanosensation. Our central hypothesis is that PIEZO1 is required to promote chondrocyte-to-osteoblast transdifferentation in postnatal trabecular bone formation and bone regeneration. Since many aspects of our working programme rely on established methodology, and since the phenotypes of mice with conditional PIEZO1 inactivation are not only unique, but also remarkably severe, we expect to gain many novel insights into the role of PIEZO1 in endochondral ossification. Our findings will not only be relevant from a basic science perspective, but they will also impact our understanding of chondrocyte-related disorders.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Cooperation Partner: David Beech