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

虽然钙和维生素D等营养因子在调节骨内稳态中的作用已被广泛研究，但锌等微量元素在骨发育和内稳态中的重要性尚未明确。在儿童中，锌缺乏与生长迟缓有关，绝经后观察到骨锌含量下降，随着年龄的增长和卧床休息。这些观察结果表明，细胞外锌可能参与骨基质的合成和矿化，锌沉积的变化可能与骨疾病有关，提示潜在的治疗机会。骨基质通常富含锌，游离锌离子在软骨内成骨部位附近积聚。细胞内锌的稳态是由大量的锌转运蛋白实现的：“Zip”家族的成员负责锌的吸收，“ZnT”家族的成员负责将锌运输到细胞器或从细胞质中挤出。锌转运蛋白突变驱动遗传性骨病患者的病理机制，如ZIP14导致人颅内骨质增生。此外，我们之前已经证明，一种名为GPR39的独特锌感应受体的功能丧失，会导致小鼠骨小梁结构异常和高矿物质与基质比的皮质骨脆弱性增加。该表型归因于胶原沉积缺陷，胶原稳定性受损和矿化特征改变。在我们的合作项目中，我们的目标是研究锌对骨基质组成和结构的作用，以及锌调节的缺失是否会导致骨细胞功能受损，从而导致骨脆弱。因此，我们将利用性别无关的研究方法，对锌补充下不同锌反应蛋白突变（ZIP14和GPR39）的小鼠进行完整的骨质量分析。胶原稳定性的分子机制和锌依赖性金属蛋白酶的作用将在成骨细胞依赖性骨基质沉积的细胞培养中确定。最后，锌在人类骨质疏松症和成骨不全症中的作用将被研究。我们结合了动物研究和分子分析（以色列）以及骨基质分析和人骨研究（德国）的专业知识，可以全面研究锌在骨骼健康中的作用。虽然我们的工作可能会产生营养建议，但胶原沉积的分子机制，稳定性和骨脆弱性的相关建议旨在产生额外的治疗靶点。

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.