A sweet solution to a tough problem: New, bio-inspired molecules as a turbo for bone regeneration

The ability of humans to constantly renew bones and thus keep them strong decreases with age and is further restricted by diseases such as osteoporosis. In order to help the ageing population, researchers are looking for new therapies to improve bone regeneration. An interdisciplinary team from the Biotechnology Centre (BIOTEC), the Faculty of Medicine and the Max Bergmann Centre for Biomaterials (MBC) at TU Dresden has now developed novel bioinspired molecules that improve bone regeneration in mice. The results were published in the scientific journal Biomaterials.

With increasing age, the ability of humans to regenerate their bones decreases. Bone fractures heal more slowly and diseases such as osteoporosis occur more frequently. This represents a major health challenge for the ageing population and an increasing socio-economic burden on society. To address this problem, research teams are looking for new therapeutic approaches that can improve bone regeneration.

A team from Dresden has used computer modelling and simulations to develop novel bioinspired molecules that improve bone regeneration in mice. They can be incorporated into biomaterials and thus introduced locally into bone defects. The novel molecules are based on glycosaminoglycans, long-chain sugars such as hyaluronic acid or heparin.

A healthy solution as a bone healing turbo

„Thanks to the work of our group and other groups, we know a specific molecular pathway, the Wnt signalling pathway, which regulates bone formation and repair. We were able to narrow it down to two brake signals that together block bone regeneration: Sclerostin and Dickkopf-1," explains Prof Lorenz Hofbauer. The major challenge for the development of drugs to improve bone healing is to switch off these two blockade proteins simultaneously and efficiently.

An interdisciplinary approach was the key to success. The Structural Bioinformatics group led by Prof. Maria Teresa Pisabarro at the Biotechnology Centre (BIOTEC) at TU Dresden and the Functional Biomaterials group led by PD Dr Vera Hintze from the Max Bergmann Centre for Biomaterials, Institute of Materials Science, combined their expertise with bone expert Prof. Lorenz Hofbauer from the Faculty of Medicine at TU Dresden.

„For several years, we have been using the possibilities of computer simulation to investigate how proteins that regulate bone formation interact with their receptors. All this with the aim of designing novel molecules that can specifically influence these interactions. We worked in tandem between the computer and the laboratory, designing and testing novel molecules, applying the results to our molecular models and learning more about the molecular properties required for our goal," explains Prof Pisabarro.

The team at Prof Hofbauer's Bone Lab then used biomaterials loaded with these molecules on bone defects in mice to test their effectiveness. The materials loaded with the new molecules proved to be significantly more effective than standard biomaterials and increased bone healing by up to 50 per cent, indicating enormous regenerative potential.

Value chain: from computer to laboratory and back

The multidisciplinary team used rational drug design to develop novel molecules with customised properties and minimal side effects. By using computational methods to predict and refine the properties of the designed molecules, the team was able to develop a series of candidates that have the greatest potential to switch off the proteins and block bone regeneration.

The expertise of the Pisabarro group enabled a detailed analysis of the three-dimensional (3D) structures of the two proteins that block bone regeneration. In this way, they were able to model the interaction of the proteins with their receptors in 3D and identify key structures, i.e. specific physico-chemical and dynamic properties that are essential for the biological interaction.

„Using molecular modelling, we designed new structures that mimic the relevant receptor interactions with the two proteins. We wanted this binding to be stronger than their natural interactions. In this way, our new molecules would both capture and effectively switch off the proteins, thereby promoting bone regeneration," explains Prof Pisabarro.

„The molecules designed by Prof. Pisabarro's group were synthesised by our colleagues at the Freie Universität Berlin and then investigated by us in terms of their protein binding properties using biophysical interaction analysis," says Dr Hintze. For each molecule, we were able to measure how strongly it binds to the proteins and how it interferes with the binding of the proteins to their natural receptors. In this way, we were able to show empirically how effectively they switch off the inhibitory proteins. Hofbauer's group tested the biological relevance of these interaction studies in a cell culture model and later in mice.

The results of these iterative tests are of great value to improve the current molecular models of the Pisabarro group and to serve as a blueprint for the development of novel and better molecules in the future. Such an approach also ensures that animal testing is minimised and only used in the final phase of the project.

On the road to drug development

The team's results represent an exciting step with significant clinical relevance. The newly developed molecules could be used to switch off proteins that block bone regeneration and lead to the development of new, more effective therapies for bone fractures and other bone diseases.

The team is continuing its successful collaboration. "We are applying for funding for a preclinical study to further develop these molecules as an innovative therapy for a study in humans," says Prof Hofbauer.

Promoting interdisciplinarity

The research work was funded by the German Research Foundation (DFG). The groups were part of the Transregio 67 Collaborative Research Centre „Functional Biomaterials for the Control of Healing Processes in Bone and Skin Tissue - from Material to Clinic (Dresden/Leipzig; 59307082—TRR67 subprojects A3, A7, A8, B2 and Z3)". Over a period of more than 12 years, the three partners, in cooperation with other groups in Germany, have developed new findings, techniques and the necessary expertise to tackle the problem of bone regeneration.

Original publication
Gloria Ruiz-Gómez, Juliane Salbach-Hirsch, Jan-Niklas Dürig, Linda Köhler, Kanagasabai Balamurugan, Sandra Rother, Sophie-Luise Heidig, Stephanie Moeller, Matthias Schnabelrauch, Giulia Furesi, Sophie Pählig, Pedro M. Guillem-Gloria, Christine Hofbauer, Vera Hintze, M. Teresa Pisabarro, Jörg Rademann, Lorenz C. Hofbauer: Rational engineering of glycosaminoglycan-based Dickkopf-1 scavengers to improve bone regeneration. Biomaterials (April 2023)
Link: https://doi.org/10.1016/j.biomaterials.2023.122105

The Biotechnology Centre (BIOTEC)
The Biotechnology Centre (BIOTEC) was founded in 2000 as a central scientific institution of TU Dresden with the aim of combining state-of-the-art research approaches in molecular and cell biology with Dresden's traditionally strong engineering sciences. Since 2016, BIOTEC has been one of three institutes of the central scientific institution Centre for Molecular and Cellular Bioengineering (CMCB) at TU Dresden. BIOTEC occupies a central position in research and teaching in the research focus area Molecular Bioengineering and combines cell biological, biophysical and bioinformatic approaches. It thus makes a decisive contribution to raising the profile of TU Dresden in the fields of health sciences, biomedicine and bioengineering.
www.tud.de/biotec
www.tud.de/cmcb

Medical Faculty Carl Gustav Carus of the Technische Universität Dresden
Dresden University Medicine, consisting of the Medical Faculty Carl Gustav Carus and the university hospital of the same name, specialises in research in the fields of oncology, metabolism as well as neurological and psychiatric diseases. Within these areas, the topics of degeneration and regeneration, imaging and technology development, immunology and inflammation as well as prevention and healthcare research are of particular interest. Internationality is a prerequisite for cutting-edge research - the University Hospital Dresden lives this concept with employees from 73 nations and numerous collaborations with research teams from all over the world.

Max Bergmann Centre for Biomaterials, Dresden
The Max Bergmann Centre for Biomaterials (MBC) is a joint research facility of TU Dresden (TUD) and the Leibniz Institute of Polymer Research (IPF). It was opened in 2002 on the campus of the Leibniz Institute of Polymer Research. Under the joint roof of its own laboratory building, the centre brings together researchers and facilities from the TUD's Institute of Materials Science and the IPF to work on biologically inspired materials. The resulting challenges combine scientific progress with industrial innovation and require a collaborative, multidisciplinary approach and cooperation across traditional structures - this is what the MBC stands for. MBC scientists are actively involved in the Centre for Regenerative Therapies Dresden (CRTD) and the Innovation Centre for Molecular Bioengineering (B CUBE). www.mbc-dresden.de

Additional materials:
Website of the research group of Prof Maria Teresa Pisabarro: https://tud.link/xksm
Website of the research group of Prof Lorenz Hofbauer: https://bone-lab.de/
Image material: https://tud.link/tdrc

Article of the "Technische Universität Dresden " from 28 April 2023