Project Details
Projekt
Molecular bases of non-classical osteogenesis imperfecta
Applicant
Professorin Dr. Sandra Pohl
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517063424
In the context of the clinical research unit ProBone (“Precision Medicine for Early-Onset Low Bone Mineral Density Disorders”), this project (P4) has a specific focus on a large and clinically relevant subgroup of early-onset low bone mineral density disorders, i.e. non-classical osteogenesis imperfecta (OI). As opposed to classical OI, genetically caused by pathogenic variants of COL1A1 or COL1A2, non-classical OI is caused by pathogenic variants in one of more than 20 other genes, which were identified in the last decades. Whereas the function of some proteins encoded by these genes has been established, the molecular knowledge about the majority of these is still limited. This is particularly true for site-2 protease, encoded by the gene MBTPS2, where pathogenic variants cause X-linked OI type XIX, but also for IFITM5, a transmembrane protein specifically expressed by osteoblasts, where a specific pathogenic variant (c.-14C>T) causes autosomal dominant OI type V. P4 will first apply a large-scale molecular profiling approach to obtain key reference knowledge about the molecular changes occurring during the course of osteoblast differentiation under physiological and pathophysiological conditions. Here we will combine, in collaboration with the ProBone projects P1 and P6, different omics approaches, i.e. transcriptomics, proteomics, lipidomics, metabolomics, which will be bioinformatically evaluated with the help of the ProBone central project 2 (CP2). Second, with respect to site-2 protease, P4 will primarily focus on a newly developed mouse model, where a Mbtps2-floxed allele is combined with the Runx2-Cre transgene to inactivate the site-2 protease specifically in osteoblast lineage cells. Since Mbtps2-deficient mice are not viable, this approach, supported by functional in vitro studies, will provide novel insights into the molecular mechanism explaining the key role of site-2 protease for bone formation and skeletal integrity. Finally, P4 will perform a series of molecular experiments to deepen our understanding regarding the structure and function of IFTIM5 and its disease-causing variants. Here the main focus will be related by the above-mentioned c.-14C>T variant, which is located in the 5´-UTR of IFITM5, thereby creating an upstream start codon and extending the N-terminus of the respective protein by 5 amino acids. For the latter, P4 will also attempt an innovative therapeutic strategy based on antisense oligonucleotides to specifically mask the novel start codon in the IFITM5 variant. This will be performed with patient-derived cells, either fibroblasts or induced pluripotent stem cells, which will be generated by the ProBone central project 1 (CP1). In a second ProBone funding period we would not only aim to extend this approach, but also to establish alternative therapeutic options, based on the results from P4 and from all other ProBone projects.
DFG Programme
Clinical Research Units
