Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations.
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.
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620, USA.
Timothy J
TJ
Bauler
Nobuhiro
N
Kamiya
Philip E
PE
Lapinski
Eric
E
Langewisch
Yuji
Y
Mishina
John E
JE
Wilkinson
Gen-Sheng
GS
Feng
Philip D
PD
King
D000375:Aging / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001842:Bone and Bones / Q000002:abnormalities* / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D002113:Calcification, Physiologic / Q000502:physiology; D002356:Cartilage / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D017353:Gene Deletion; D006410:Hematopoiesis / Q000502:physiology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000502:physiology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency* / Q000378:metabolism; D015398:Signal Transduction; D013121:Spinal Curvatures / Q000097:blood / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D016019:Survival Analysis; D015431:Weight Loss
D015415:Biomarkers; D016173:Macrophage Colony-Stimulating Factor; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse