Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Dis Model Mech. 2013 Nov;6(6):1448-58. doi: 10.1242/dmm.012849. Epub 2013 Sep 25.
In mice, induced global disruption of the Ptpn11 gene, which encodes the SHP-2 tyrosine phosphatase, results in severe skeletal abnormalities. To understand the extent to which skeletal abnormalities can be attributed to perturbation of SHP-2 function in bone-forming osteoblasts and chondrocytes, we generated mice in which disruption of Ptpn11 is restricted to mesenchymal stem cells (MSCs) and their progeny, which include both cell types. MSC-lineage-specific SHP-2 knockout (MSC SHP-2 KO) mice exhibited postnatal growth retardation, limb and chest deformity, and calvarial defects. These skeletal abnormalities were associated with an absence of mature osteoblasts and massive chondrodysplasia with a vast increase in the number of terminally differentiated hypertrophic chondrocytes in affected bones. Activation of mitogen activated protein kinases (MAPKs) and protein kinase B (PKB; also known as AKT) was impaired in bone-forming cells of MSC SHP-2 KO mice, which provides an explanation for the skeletal defects that developed. These findings reveal a cell-autonomous role for SHP-2 in bone-forming cells in mice in the regulation of skeletal development. The results add to our understanding of the pathophysiology of skeletal abnormalities observed in humans with germline mutations in the PTPN11 gene (e.g. Noonan syndrome and LEOPARD syndrome).
在小鼠中，诱导 Ptpn11 基因（编码 SHP-2 酪氨酸磷酸酶）的全局缺失会导致严重的骨骼异常。为了了解骨骼异常在多大程度上归因于成骨细胞和成软骨细胞中 SHP-2 功能的失调，我们生成了 Ptpn11 缺失仅限于间充质干细胞（MSCs）及其祖细胞（包括这两种细胞类型）的小鼠。MSC 谱系特异性 SHP-2 敲除（MSC SHP-2 KO）小鼠表现出出生后生长迟缓、四肢和胸部畸形以及颅盖骨缺陷。这些骨骼异常与成熟成骨细胞的缺失以及大量软骨发育不良有关，受影响骨骼中的终末分化的肥大软骨细胞数量大量增加。MSC SHP-2 KO 小鼠成骨细胞中丝裂原激活蛋白激酶（MAPKs）和蛋白激酶 B（PKB；也称为 AKT）的激活受到损害，这为发展中的骨骼缺陷提供了一个解释。这些发现揭示了 SHP-2 在调节骨骼发育过程中在小鼠成骨细胞中的自主作用。这些结果增加了我们对具有 PTPN11 基因突变（例如 Noonan 综合征和 LEOPARD 综合征）的人类中观察到的骨骼异常的病理生理学的理解。
