Hematological defects in the oc/oc mouse, a model of infantile malignant osteopetrosis
Hematological defects in the oc/oc mouse, a model of infantile malignant osteopetrosis
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DOI：
10.1038/sj.leu.2403449
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发表时间：
2004-09-01
期刊：
影响因子：
11.4
通讯作者：
Carle, GF
中科院分区：
文献类型：
--
作者：
Blin-Wakkach, C;Wakkach, A;Carle, GF
摘要婴儿恶性石骨症是一种罕见且致命的疾病，其特徴为无活性骨胶原导致骨吸收缺失。受影响的患者表现出骨量增加和血液学缺陷。骨硬化oc/oc小鼠显示出与IMO患者中观察到的骨表型相似的骨表型，并且相同的基因Tcirg 1在该模型和大多数这些患者中发生突变。因此，我们在oc/oc小鼠中探索了骨微环境扰动对造血的影响。我们发现，骨髓单核细胞分化增加，导致OCL和树突状细胞的数量增加。在oc/oc小鼠的骨髓中，B淋巴细胞生成在前B阶段被阻断，导致低成熟B细胞数量。T细胞活化也受到影响，脾CD 4（+）T细胞分泌IFN γ减少。这些改变与骨髓中的低IL-7表达相关。所有这些数据表明，缺乏骨吸收的oc/oc小鼠骨髓和淋巴细胞生成的重要后果，导致免疫缺陷的形式。因此，oc/oc小鼠是了解IMO患者中描述的血液学缺陷并获得新的治疗策略的合适模型。
Infantile malignant osteopetrosis (IMO) is a rare and lethal disease characterized by an absence of bone resorption due to inactive OCLs. Affected patients display an increased bone mass and hematological defects. The osteopetrotic oc/oc mouse displays a bone phenotype similar to the one observed in IMO patients, and the same gene, Tcirg1, is mutated in this model and in the majority of these patients. Therefore, we explored in oc/oc mice the consequences of the perturbed bone microenvironment on hematopoiesis. We show that the myelomonocytic differentiation is increased, leading to an elevated number of OCLs and dendritic cells. B lymphopoiesis is blocked at the pro-B stage in the bone marrow of oc/oc mouse, leading to a low mature B-cell number. T-cell activation is also affected, with a reduction of IFNgamma secretion by splenic CD4(+) T cells. These alterations are associated with a low IL-7 expression in bone marrow. All these data indicate that the lack of bone resorption in oc/oc mice has important consequences in both myelopoiesis and lymphopoiesis, leading to a form of immunodeficiency. The oc/oc mouse is therefore an appropriate model to understand the hematological defects described in IMO patients, and to derive new therapeutic strategies.