Project Details
Projekt
Molecular understanding of fracture healing in early-onset low BMD disorders
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517063424
Deterioration of bone quality is associated with an increased fracture risk, which is also the hallmark commonality of the heterogeneous patient population with early-onset low bone mineral density (BMD). Several risk factors have been identified that predispose to impaired fracture healing, including not only lifestyle factors and immune or metabolic disorders, but also early-onset low BMD disorders. Although there is anecdotal evidence of impaired bone healing in individuals carrying certain pathologic gene variants, there has been no systematic evaluation of bone regeneration in early-onset low BMD disorders. Because a fracture event has a severe, often disabling impact on the quality of life of affected individuals, there is an urgent need to understand the basis of impaired bone regeneration in affected individuals. Most importantly, it is necessary to define how specific gene variants affect the multi-step process of fracture healing at the cellular and molecular level, and whether specific pharmacological interventions are potentially suitable to improve bone regeneration. In the context of the clinical research unit ProBone, we therefore aim to define variant-specific healing outcomes, further understand their underlying pathophysiology, enable the development of specific therapeutic approaches, and correlate our experimental findings in mouse models with clinical data. First, we will use our highly standardized femoral osteotomy fracture model stabilized by an external fixator to characterize the bone healing process in selected mouse models of early-onset low BMD disorders. Second, because bone regeneration is highly dependent on inflammatory responses and the provision of sufficient energy by metabolic processes that are regulated by specific pathogenic variants present in early-onset low BMD disorders, we will delineate the respective impact of altered immune cell function and metabolic control on the outcome of bone healing in vivo and in vitro. Third, we will take advantage of treatment regimens previously shown to be effective in counteracting alterations in i) impaired mineralization, ii) insufficient osteogenesis, iii) excessive callus remodeling, iv) insufficient energy supply/utilization, or v) hyper- or hypoinflammation in bone repair and selectively apply them to mouse models of early-onset low BMD. Finally, we aim to demonstrate the clinical relevance of our key experimental findings, identified not only in this, but also in other ProBone projects, in samples of altered bone healing derived from patients with/without early-onset low BMD disorders compared to healthy bone samples. Taken together, in close collaboration with the other ProBone groups investigating genetic, metabolic and immunological aspects, this project is designed to provide a systematic and in-depth analysis of bone regeneration in early-onset low BMD disorders with high translational importance.
DFG Programme
Clinical Research Units
