Induced global disruption of the Ptpn11 gene in mice that 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 (MSC) and their progeny that 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 and protein kinase B/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 are relevant to an understanding of the pathophysiology of skeletal abnormalities observed in humans with germline mutations in the PTPN11 gene.
- Received April 30, 2013.
- Accepted September 23, 2013.
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