Development of severe skeletal defects in induced SHP-2-deficient adult mice

A model of skeletal malformation in humans with SHP-2 mutations

Timothy J. Bauler, Nobuhiro Kamiya, Philip E. Lapinski, Eric Langewisch, Yuji Mishina, John E. Wilkinson, Gen Sheng Feng, Philip D. King

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)228-239
Number of pages12
JournalDMM Disease Models and Mechanisms
Volume4
Issue number2
DOIs
StatePublished - Mar 2011
Externally publishedYes

Fingerprint

Tissue homeostasis
Bone
Macrophage Colony-Stimulating Factor Receptors
RANK Ligand
Signal transduction
Defects
Mutation
Protein Tyrosine Phosphatases
Macrophage Colony-Stimulating Factor
Cartilage
Cell Surface Receptors
Protein Kinases
LEOPARD Syndrome
Chemical activation
Noonan Syndrome
Tissue
Kyphosis
Hematopoiesis
Scoliosis
Osteoclasts

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Neuroscience (miscellaneous)

Cite this

Development of severe skeletal defects in induced SHP-2-deficient adult mice : A model of skeletal malformation in humans with SHP-2 mutations. / Bauler, Timothy J.; Kamiya, Nobuhiro; Lapinski, Philip E.; Langewisch, Eric; Mishina, Yuji; Wilkinson, John E.; Feng, Gen Sheng; King, Philip D.

In: DMM Disease Models and Mechanisms, Vol. 4, No. 2, 03.2011, p. 228-239.

Research output: Contribution to journalArticle

Bauler, TJ, Kamiya, N, Lapinski, PE, Langewisch, E, Mishina, Y, Wilkinson, JE, Feng, GS & King, PD 2011, 'Development of severe skeletal defects in induced SHP-2-deficient adult mice: A model of skeletal malformation in humans with SHP-2 mutations', DMM Disease Models and Mechanisms, vol. 4, no. 2, pp. 228-239. https://doi.org/10.1242/dmm.006130
Bauler, Timothy J. ; Kamiya, Nobuhiro ; Lapinski, Philip E. ; Langewisch, Eric ; Mishina, Yuji ; Wilkinson, John E. ; Feng, Gen Sheng ; King, Philip D. / Development of severe skeletal defects in induced SHP-2-deficient adult mice : A model of skeletal malformation in humans with SHP-2 mutations. In: DMM Disease Models and Mechanisms. 2011 ; Vol. 4, No. 2. pp. 228-239.
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