Abstract
SUMMARYIn 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).
Highlights
Src homology-2 protein tyrosine phosphatase (SHP-2), encoded by the PTPN11 gene in humans, is a ubiquitously expressed intracellular signaling molecule that contains a pair of N-terminal protein phosphotyrosine-binding SH2 domains and a C-terminal protein tyrosine phosphatase (PTP) domain (Chong and Maiese, 2007; Matozaki et al, 2009)
The authors used an inducible murine model of SHP-2 deficiency to demonstrate a crucial role for SHP-2 in the development of osteoclasts – a type of bone cell that is involved in bone resorption
The authors disrupted the Ptpn11 gene in mesenchymal stem cells (MSCs) – the precursors of both osteoblasts and chondrocytes – to investigate whether the role of SHP-2 in bone development is restricted to specific cells
Summary
Src homology-2 protein tyrosine phosphatase (SHP-2), encoded by the PTPN11 gene in humans, is a ubiquitously expressed intracellular signaling molecule that contains a pair of N-terminal protein phosphotyrosine-binding SH2 domains and a C-terminal protein tyrosine phosphatase (PTP) domain (Chong and Maiese, 2007; Matozaki et al, 2009). SHP-2 functions downstream of numerous cell surface receptors to regulate diverse cellular responses, including growth, survival, proliferation and differentiation. One principal way in which SHP-2 is known to act is to promote the coupling of cell surface receptors to activation of the Ras small GTP-binding protein (Dance et al, 2008). Ras triggers the activation of ERK mitogen activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3K)–protein-kinase-B (PKB/AKT) signaling pathways that regulate cell responses in part through the mobilization of transcription factors (Buday and Downward, 2008). SHP-2 can function as a negative regulator of intracellular signal transduction. SHP-2 has been shown to inhibit the activation of STAT transcription factors, the p38 MAPK kinase
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