A novel mouse model for osteopetrosis

骨化症是一种罕见的，通常是遗传性的人类骨骼疾病。脆性骨骼、发育迟缓、骨骼畸形和造血功能受损是患者的典型临床特征。尽管骨髓移植正在进行临床试验，但目前还没有得到批准的治疗方法。破骨细胞数量和/或活性减少是骨化症的细胞特征，并导致不能正确地吸收骨。骨化病的小鼠模型很少，而且没有一个直接关注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-/-小鼠身上观察到了一种强烈的骨化表型。SWAP-70是一种PIP3结合、RhoGTP酶相互作用、F-肌动蛋白结合蛋白，在造血细胞中表达。SWAP-70在F-肌动蛋白重排中发挥作用，控制细胞的形状、迁移、整合素介导的黏附、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，我们推测该蛋白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发挥关键作用，特别是在F-肌动蛋白重排和整合素介导的黏附中，是破骨细胞性骨吸收所必需的。最初的实验表明，SWAP-70-/单核细胞来源的破骨细胞有缺陷的骨吸收支持这一假设。我们请求支持研究这种新的小鼠骨化症模型，目的是从根本上对骨和破骨细胞生物学产生新的见解，从而更好地了解骨化症，即它的起源及其对骨骼和造血系统的影响。

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.