Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations.
Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations.
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DOI：
10.1242/dmm.006130
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发表时间：
2011-03
影响因子：
4.3
通讯作者：
King PD
中科院分区：
文献类型：
--
作者：
Bauler TJ;Kamiya N;Lapinski PE;Langewisch E;Mishina Y;Wilkinson JE;Feng GS;King PD
SHP-2（由PTPN 11编码）是一种广泛表达的蛋白酪氨酸磷酸酶，是多种不同细胞表面受体进行信号转导所必需的。具有生殖系SHP-2突变的人类发展努南综合征或LEOPARD综合征，其特征在于心血管、神经和骨骼异常。为了研究SHP-2如何调节正常成年人的组织稳态，我们使用了一种条件性SHP-2小鼠突变体，其中SHP-2表达的丧失在多个组织中响应于药物施用而被诱导。SHP-2的诱导缺失导致造血功能受损、体重减轻和死亡。最引人注目的是，诱导SHP-2缺陷小鼠出现严重的骨骼异常，包括脊柱后凸和脊柱侧凸。颅骨畸形与软骨的改变和骨小梁质量的显著增加有关。破骨细胞基本上不存在于SHP-2缺陷小鼠的骨骼中，因此解释了骨硬化表型。体外研究表明，在SHP-2缺陷小鼠中，由巨噬细胞集落刺激因子（M-CSF）和核因子κ B配体受体激活剂（RANKL）刺激的破骨细胞生成是缺陷的。至少部分地，这是由M-CSF诱导的造血前体细胞中促存活蛋白激酶AKT的活化中对SHP-2的需要来解释的。这些发现说明了SHP-2在成人骨骼生长和重塑中的重要作用，并揭示了一些相关的细胞和分子机制。该模型预计将进一步用于了解SHP-2如何调节骨骼形态发生，这可能导致开发新的治疗方法，用于治疗SHP-2突变的人类患者的骨骼畸形。
SHP-2 (encoded by PTPN11) is a ubiquitously expressed protein tyrosine phosphatase required for signal transduction by multiple different cell surface receptors. Humans with germline SHP-2 mutations develop Noonan syndrome or LEOPARD syndrome, which are characterized by cardiovascular, neurological and skeletal abnormalities. To study how SHP-2 regulates tissue homeostasis in normal adults, we used a conditional SHP-2 mouse mutant in which loss of expression of SHP-2 was induced in multiple tissues in response to drug administration. Induced deletion of SHP-2 resulted in impaired hematopoiesis, weight loss and lethality. Most strikingly, induced SHP-2-deficient mice developed severe skeletal abnormalities, including kyphoses and scolioses of the spine. Skeletal malformations were associated with alterations in cartilage and a marked increase in trabecular bone mass. Osteoclasts were essentially absent from the bones of SHP-2-deficient mice, thus accounting for the osteopetrotic phenotype. Studies in vitro revealed that osteoclastogenesis that was stimulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) was defective in SHP-2-deficient mice. At least in part, this was explained by a requirement for SHP-2 in M-CSF-induced activation of the pro-survival protein kinase AKT in hematopoietic precursor cells. These findings illustrate an essential role for SHP-2 in skeletal growth and remodeling in adults, and reveal some of the cellular and molecular mechanisms involved. The model is predicted to be of further use in understanding how SHP-2 regulates skeletal morphogenesis, which could lead to the development of novel therapies for the treatment of skeletal malformations in human patients with SHP-2 mutations.
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