A novel mouse model for osteopetrosis

一种新型骨石症小鼠模型

• 批准号: 122203228
• 负责人: Professor Dr. Rolf Jessberger
• 金额: --
• 依托单位: Institut für Physiologische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/122203228?language=en
• 关键词: novel; mouse; model; osteopetrosis

Osteopetrosis is a rare, often inherited bone disease in humans. Brittle bones, stunted growth, bone deformities, and impaired hematopoiesis are characteristic clinical features of affected patients. There is currently no approved therapy, although bone marrow transplantation is being investigated in clinical trials. A decreased number and/or activity of osteoclasts are the cellular hallmarks of osteopetrosis and results in the inability to properly resorb bone. Few mouse models exist for osteopetrosis, and none directly focuses on the F-actin cytoskeletal rearrangements, which are key to osteoclast function. We recently observed a strong osteopetrotic phenotype in the Swap-70-/- mouse. SWAP-70 is a PIP3-binding, RhoGTPaseinteracting, F-actin binding protein expressed in hematopoietic cells. SWAP-70 functions in F-actin rearrangements and controls cell shape, migration, integrinmediated adhesion, homing and related processes. Based on our extensive knowledge of the features of SWAP-70 in the hematopoietic system, we hypothesize that this protein, which we recently found to be expressed in osteoclasts and to localize to F-actin rings, plays a key role in osteoclast biology, specifically in F-actin rearrangement and integrin-mediated adhesion required for osteoclastic bone resorption. Initial experiments showing defective bone resorption by Swap-70-/- monocyte-derived osteoclasts support this hypothesis. We ask for support to investigate this new mouse model for osteopetrosis with the aim to generate fundamentally new insights into bone and osteoclast biology and thus to better understand osteopetrosis, i.e. its origin and its consequences for the bone and hematopoietic systems.

石骨症是一种罕见的，往往是遗传性的骨骼疾病在人类。骨脆、生长发育迟缓、骨畸形和造血功能受损是受累患者的典型临床特征。目前还没有批准的治疗方法，尽管骨髓移植正在临床试验中进行研究。破骨细胞的数量和/或活性降低是石骨症的细胞标志，并导致无法正确吸收骨。很少有小鼠模型存在骨硬化症，没有直接关注的F-肌动蛋白细胞骨架重排，这是破骨细胞功能的关键。我们最近在Swap-70-/-小鼠中观察到强烈的骨硬化表型。SWAP-70是在造血细胞中表达的PIP 3结合、RhoGTP酶相互作用、F-肌动蛋白结合蛋白。SWAP-70在F-肌动蛋白重排中起作用，并控制细胞形状、迁移、整合素介导的粘附、归巢和相关过程。基于我们对SWAP-70在造血系统中的功能的广泛了解，我们假设这种蛋白质，我们最近发现在破骨细胞中表达并定位于F-肌动蛋白环，在破骨细胞生物学中起着关键作用，特别是在F-肌动蛋白重排和整联蛋白介导的骨细胞骨吸收所需的粘附。初步实验显示Swap-70-/-单核细胞衍生的破骨细胞的骨吸收缺陷支持这一假设。我们要求支持研究这种新的石骨症小鼠模型，目的是从根本上对骨和破骨细胞生物学产生新的见解，从而更好地了解石骨症，即其起源及其对骨和造血系统的影响。