Molecular role of PIEZO1 in endochondral ossification

PIEZO1在软骨内骨化中的分子作用

• 批准号: 467458614
• 负责人: Professorin Dr. Anita Ignatius
• 金额: --
• 依托单位: Institut für Osteologie und Biomechanik (IOBM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/467458614?language=en
• 关键词: Molecular; role; PIEZO1; endochondral; ossification

Skeletal development, growth and remodeling are highly complex processes involving many different cell types with unique functions. The majority of the axial and appendicular skeleton develops by endochondral ossification, a process depending on chondrocytes, which produce a cartilage intermediate that is subsequently replaced by bone. We have previously identified a key role of the mechanically activated ion channel PIEZO1 in both, skeletal remodeling and endochondral ossification. Whereas the first function of PIEZO1 depends on its expression in bone-embedded osteocytes, its role in endochondral ossification is mediated by PIEZO1 expression in growth plate chondrocytes. More specifically, our collective analyses of conditional mouse models with PIEZO1 deficiency in different skeletal cell types has demonstrated that chondrocyte-specific PIEZO1 inactivation strongly impairs postnatal trabecular bone formation. Moreover, molecular experiments with cultured bone cells suggested that PIEZO1 specifically controls the chondrocyte-to-osteoblast transdifferentation process. The primary goal of this project is to fully uncover the molecular role of PIEZO1 in chondrocytes, also taking advantage of additional mouse models allowing inducible PIEZO1 inactivation and lineage tracing. We will also combine the chondrocyte-specific PIEZO1 inactivation with other genetic modifications to specify the role of potential downstream mediators. Since the process of endochondral ossification is also recapitulated during fracture healing, we want to take advantage of our existing expertise in analyzing this process in a controlled osteotomy model. Finally, cell culture experiments will be performed to link the in vivo findings to impaired mechanosensation. Our central hypothesis is that PIEZO1 is required to promote chondrocyte-to-osteoblast transdifferentation in postnatal trabecular bone formation and bone regeneration. Since many aspects of our working programme rely on established methodology, and since the phenotypes of mice with conditional PIEZO1 inactivation are not only unique, but also remarkably severe, we expect to gain many novel insights into the role of PIEZO1 in endochondral ossification. Our findings will not only be relevant from a basic science perspective, but they will also impact our understanding of chondrocyte-related disorders.

骨骼的发育、生长和重塑是非常复杂的过程，涉及许多不同类型的细胞，具有独特的功能。大多数轴向和附件骨骼是通过软骨内骨化发展起来的，这是一个依赖于软骨细胞的过程，软骨细胞产生一种软骨中间体，随后被骨取代。我们之前已经确定了机械激活的离子通道PIEZO1在骨骼重塑和软骨内成骨中的关键作用。虽然PIEZO1的第一功能依赖于其在骨嵌入的骨细胞中的表达，但其在软骨内成骨中的作用是通过PIEZO1在生长板软骨细胞中的表达来介导的。更具体地说，我们对不同骨骼细胞类型的PIEZO1缺乏的条件性小鼠模型的集体分析表明，软骨细胞特异性的PIEZO1失活强烈损害出生后的骨小梁形成。此外，对培养的骨细胞进行的分子实验表明，PIEZO1特异性地控制软骨细胞向成骨细胞的跨分化过程。该项目的主要目标是充分揭示PIEZO1在软骨细胞中的分子作用，并利用其他允许诱导PIEZO1失活和谱系追踪的小鼠模型。我们还将把软骨细胞特异性的PIEZO1失活与其他基因修饰结合起来，以确定潜在的下游介体的作用。由于软骨内骨化的过程在骨折愈合过程中也被重述，我们希望利用我们现有的专业知识在受控截骨模型中分析这一过程。最后，将进行细胞培养实验，将体内的发现与受损的机械感觉联系起来。我们的中心假设是，PIEZO1在出生后的骨小梁形成和骨再生中需要促进软骨细胞到成骨细胞的跨分化。由于我们的工作计划的许多方面依赖于既定的方法，而且条件PIEZO1失活小鼠的表型不仅独特，而且非常严重，我们希望对PIEZO1在软骨内成骨中的作用获得许多新的见解。我们的发现不仅从基础科学的角度来看是相关的，而且还将影响我们对软骨细胞相关疾病的理解。