Influence of cold-induced energy expenditure on bone remodeling

• Applicants: Professor Dr. Jörg Heeren; Professor Thorsten Schinke, Ph.D.
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458245644

The existence of an intimate link between bone remodelling and energy metabolism is supported by various studies in genetically modified mouse models, but also by clinical observations. For instance, obesity is often associated with increased bone mineral density, whereas low body weight is a risk factor for osteoporotic fractures. Moreover, since adipocytes and bone-forming osteoblasts share the same progenitor cells, decreased osteoblastogenesis is often linked to increased bone marrow adiposity in osteoporotic individuals. Finally, increased fracture risk is frequently observed in patients with type II diabetes, yet the cellular and molecular mechanisms explaining this association are not fully understood. Previous work the group of Prof. Heeren has demonstrated that an induction of brown adipose tissue activity by cold exposure has beneficial effects on insulin-sensitivity, glucose and lipid homeostasis, in mice and in humans. In a collaboration between our two groups we have further observed, that mice housed in a cold environment lose about 50% of their trabecular bone within four weeks, whereas cold exposure for one week immediately reduces osteoblast-mediated bone formation. Our hypothesis is that this negative influence of cold exposure on bone formation is caused by increased production of (a) specific molecule(s), whose identification is the major goal of our project. In our work programme we will first perform in-depth analyses regarding immediate and long-term influences of cold exposure on various metabolic and bone remodelling parameters in wildtype mice, which also includes lipidomic analyses. After having defined the optimal conditions to monitor specific readouts, we will take advantage of different genetically modified mouse models to evaluate if the inactivation of specific genes and/or pathways impairs the metabolic and bone remodelling response to cold exposure. Finally, we will perform cell culture experiments with primary osteoblasts in order to study the influence of candidate mediators of such a response at a molecular level. Our project, which mostly relies on established methods, will generate entirely novel insights into the interaction between energy metabolism and bone remodelling, which should be of broad interest for the respective research areas. Moreover, should we succeed with the identification of a cold-induced molecule inhibiting bone formation, the blockade of such a molecule or its receptor could be an attractive approach for osteoanabolic treatment of bone loss disorders.

• DFG Programme: Research Grants