Project Details
Projekt
Impact of specific gene variants on growth plate and articular cartilage in early-onset low BMD disorders
Applicant
Privatdozent Dr. Tim Rolvien
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517063424
As an integral part of the clinical research unit ProBone ("Precision Medicine for Early-Onset Low Bone Mineral Density Disorders"), this project (P9) aims to explore osteochondral interactions within the growth plate and the joint, through in-depth clinical examination of affected patients, analysis of tissue biopsies, phenotyping of mouse models, and establishment of cellular systems. Since a considerable subset of patients with early-onset low BMD (P1, P2 and P5) additionally present with skeletal dysplasia and/or osteoarthritis, it is of utmost relevance that these patients will undergo an in-depth orthopaedic assessment, including high-resolution imaging, synovial analysis, application of physician-based clinical scores, and patient-reported outcome measures. The patient cohort comprises diverse phenotypes of skeletal dysplasia and early-onset osteoarthritis, but also patients with pathogenic gene variants known to be associated with subtypes of chondrodysplasia. Furthermore, to provide a more detailed understanding of the mechanistic aspects of osteochondral pathologies in affected patients, we will optimize the protocols to differentiate human induced pluripotent stem cells (hiPSCs) into chondrocytes in close collaboration with CP1. Another focus of this project is to obtain bone-cartilage samples and perform a multiscale ultrastructural analysis during orthopaedic surgery in patients with early-onset low BMD and cartilage pathologies. We will take advantage of our expertise by assessing articular cartilage (OARSI score, thickness, mineralization) as well as the underlying subchondral and trabecular bone using µ-CT (microarchitecture), undecalcified histomorphometry, quantitative backscattered electron imaging (qBEI, bone mineral density distribution), nanoindentation (biomechanics), and osteocyte lacunocanalicular network characterization. Finally, in close cooperation with P1, P4, P5 and P8, we will study joint phenotypes and osteochondral interactions in several genetically modified mouse models of different types of osteogenesis imperfecta (Col1a2oim/oim, Mbtps2fl/fl;Runx2-Cre, Wnt1G177C/G177C), lysosomal storage disorders (Gnptgko, Gnptabc.3440_3441del), or hypophosphatasia (TnsalpE191K). Through the knowledge gained, we aim to decipher the influence of specific low BMD gene variants on endochondral ossification and cartilage biology. In doing so, we also intend to gain deeper insight into the role of low BMD and specifically subchondral bone homeostasis, at microstructural and genetic levels, in osteoarthritis development. Our overall goal is to discover disease genes and their respective mechanisms and to develop more individualized orthopedic treatments for affected patients.
DFG Programme
Clinical Research Units
