Deletion of SHP-2 in mesenchymal stem cells causes growth retardation, limb and chest deformity, and calvarial defects in mice.
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).
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Philip E
PE
Lapinski
Melissa F
MF
Meyer
Gen-Sheng
GS
Feng
Nobuhiro
N
Kamiya
Philip D
PD
King
D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities*; D005317:Fetal Growth Retardation / Q000235:genetics*; D017880:Limb Deformities, Congenital / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D013909:Thorax / Q000002:abnormalities*
D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11