Understanding the interaction between biomechanical loading and bone remodeling

• Applicants: Professor Dr. Jan Baumbach; Professor Dr. Axel Karl Walch
• Subject Area: Anatomy and Physiology ; Medical Informatics and Medical Bioinformatics
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570483888

Osteoporosis is a major socioeconomic health burden with about 200 million patients worldwide. Imbalances in bone remodeling and uncoupled remodeling are key mechanisms in the pathogenesis of osteoporosis. Bone remodeling is a cyclic renewal mechanism in which bone formation follows bone resorption in the same skeletal site. For poorly understood reasons, the quantum of bone formed matches the amount of bone resorbed under normal conditions in healthy adults, i.e., resorption and formation are coupled and the remodeling balance is zero. Most of the work attempting to elucidate the molecular mechanisms underlying the regulation of bone remodeling has been done in mice, a species lacking Haversian remodeling. Here, we aim to overcome the limitations of mouse models by focusing on sheep, a species characterized by Haversian bone remodeling similar to humans. We will employ a novel, reversible stress-shielding model in the ovine tibia to test the hypothesis that all steps of bone remodeling, including bone resorption, coupling, and bone formation are orchestrated by biomechanical signals. By harnessing the power of newly developed spatial genomics technologies in bone in combination with biomechanical modeling and computational systems biology, we will further explore the nature of the biochemical signals and the pathways involved in the coupling mechanism and in the regulation of bone remodeling. In our reversible stress-shielding model in sheep, stress shielding is achieved by unloading a several centimeter-wide part of cortical bone in the tibial shaft by means of a carbon plate attached to the medial aspect of the tibia with locking screws. Removal of the plate results in re-loading of the previously unloaded bone. To uncover the biological responses to altered strain energy densities in vivo, we will map in situ metabolic and transcriptomic profiles as well as histomorphometric changes in bone remodeling units induced by experimental changes in loading to μ-finite element (μFE) models. The innovativeness and relevance of the project are extremely high. There has never been an integration of spatial genomics and histomorphometry data with μFE models in an experimental stressshielding model in a remodeling species. The project will significantly advance our knowledge of the mechanism involved in the regulation of bone remodeling by biomechanical loading. Improved knowledge of the cellular and molecular mechanisms controlling bone remodeling may eventually lead to new possibilities for the prevention, diagnosis, and treatment of osteoporosis. The project combines the expertise of Reinhold Erben in bone biology, of Philippe Zysset in bone biomechanics, of Peter Varga in implant models, of Axel Walch in spatial metabolomics, and of Jan Baumbach in computational systems biology.

• DFG Programme: Research Grants
• International Connection: Austria, Switzerland
• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Cooperation Partners: Professor Dr. Reinhold Erben; Privatdozent Dr. Peter Varga; Professor Dr. Philippe Zysset