TGF-β signaling and cellular senescence in the disease mechanism and therapy of gerodermia osteodysplastica, a form of early-onset osteoporosis

• Applicant: Dr. Björn Fischer-Zirnsak, since 6/2020
• Subject Area: Human Genetics ; Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445106629

Mutations in GORAB lead to gerodermia osteodysplastica (GO), a rare progeroid disorder characterized by early-onset osteoporosis and spontaneous fractures, for which no efficient therapy is available. Our previous work demonstrated a role of GORAB in intra-Golgi trafficking and reduced glycanation of proteoglycans, altered extracellular matrix (ECM) organization and elevated TGF-β signaling in mouse models of GO. Like in age-related osteoporosis, this leads to an accumulation of senescent cells. We want to further dissect whether ECM alterations or rather cell-intrinsic perturbations are initiating this mechanism. To this end, the bone phenotype, TGF-β signaling, and cellular senescence will be monitored after inducible Gorab inactivation in GorabiCre mutants after a normal ECM has been established. Complementary in vitro approaches based on cell models allowing timed perturbation or activation of central nodes of the pathway will be used in addition. Moreover, using the GorabPrx1 mouse model we will explore the therapeutic potential of dampening TGF-β signaling and cellular senescence by the anti-TGF-β antibody 1D11 and inactivation of Cdkn2a, respectively. In order to fully capture the effects of these interventions, especially on the amount and origin of senescent cells, we will include a single cell sequencing approach focusing on the bone marrow stroma containing osteogenic precursors. Newly identified factors contributing to the disease pathway will be further evaluated in in vitro experiments and in other mouse models for progeroid connective tissue disorders. We think that our project addresses key aspects of development and aging that have an impact beyond GO.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Uwe Kornak, until 6/2020