The role of Zinc and Zinc-dependent G Protein-coupled Receptor (GPR39) on the structure and composition of bone

• Applicant: Professor Dr. Björn Busse
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 491625319

Although the role of nutritional factors such as calcium and vitamin D in regulation of bone homeostasis has been widely studied, the importance of trace elements such as zinc in bone development and homeostasis is not well defined yet. In children, zinc deficiency is associated with growth retardation, and decreased bone zinc content is observed post-menopause, with aging and bed rest. These observations suggest that extracellular zinc may be involved in bone matrix synthesis and mineralization, and changes in zinc deposition may associate with bone diseases suggesting a potential therapeutic opportunity.Bone matrix is generally rich in zinc content and free zinc ions were shown to accumulate in proximity to sites of endochondral ossification. Zinc homeostasis in cells is achieved by a large number of zinc transporters: members of the “Zip” family are responsible for zinc absorption and members of the “ZnT” family are responsible for transport of zinc into organelles or its extrusion from the cytoplasm. Mutations in zinc transporters drive pathologic mechanisms of patients with inherited bone diseases e.g. ZIP14 causing human hyperostosis cranialis interna. In addition, we have shown previously that loss of function of a unique zinc sensing receptor named GPR39, results in abnormal trabecular bone architecture and increased cortical bone fragility with high mineral-to-matrix ratio in mice. The phenotype was attributed to a defect in collagen deposition, impaired collagen stability and altered mineralization characteristics. Within our collaborative project we aim to investigate the role of zinc for bone matrix composition and structure and if loss of zinc regulation causes impaired bone cell function leading to bone fragility. Therefore, we are going to utilize sex-independent investigations on mice with different zinc responsive protein mutations (ZIP14 and GPR39) under zinc supplementation for a complete bone quality analysis. The molecular mechanism of collagen stability and the role of zinc-dependent metalloproteinases will be determined in cell cultures of osteoblast-dependent bone matrix deposition. Finally, the role of zinc in human bone pathologies – osteoporosis and osteogenesis imperfecta – will be investigated.Our combined expertise of animal studies and molecular analyses on one hand (Israel) and bone matrix analyses and human bone studies on the other hand (Germany) allows a comprehensive investigation on the role of zinc in bone health. While nutritional advice might be generated by our work, the molecular mechanisms on collagen deposition, stability and related suggestions on bone fragility aim to generate an additional therapeutic target.

• DFG Programme: Research Grants
• International Connection: Belgium, Israel
• Cooperation Partners: Gretl Hendrickx, Ph.D.; Professor Dr. Wim van Hul
• International Co-Applicant: Noam Levaot, Ph.D.