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Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations.

Bauler TJ, Kamiya N, Lapinski PE, Langewisch E, Mishina Y, Wilkinson JE, Feng GS, King PD - Dis Model Mech (2010)

Bottom Line: Induced deletion of SHP-2 resulted in impaired hematopoiesis, weight loss and lethality.Skeletal malformations were associated with alterations in cartilage and a marked increase in trabecular bone mass.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620, USA.

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.

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Increased and disorganized bone and cartilage in induced SHP-2-deficient mice. Shown are representative images of L4 vertebrae and femora of moribund tamoxifen-injected ptpn11fl/fl ert2-cre mice and ptpn11fl/fl littermate controls. Mice were injected with tamoxifen at 7 weeks of age and analysis was performed at 12 weeks of age. Top and middle panels are stained with H&E, and bottom panels are stained with Alcian blue to highlight cartilage. Scale bars: 1 mm in top panels, 500 μm in L4 vertebrae middle panels, and 200 μm in femora middle panels and all bottom panels. The amount of trabecular bone (t) is dramatically increased in ptpn11fl/fl ert2-cre vertebrae and femora. A region of remodeled (r) cortical bone (c) in femora of ptpn11fl/fl ert2-cre mice shows disorganized bone in this region compared with the same region in the control. Remains of ectopic cartilaginous elements (e) were identified in the trabecular bone region and ectopic cartilage formation (cf) was identified next to growth plates (g) in ptpn11fl/fl ert2-cre mice. The columnar formation of growth plates was disorganized in ptpn11fl/fl ert2-cre mice and the area of hypertrophic chondrocytes (hc) was elongated.
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f5-0040228: Increased and disorganized bone and cartilage in induced SHP-2-deficient mice. Shown are representative images of L4 vertebrae and femora of moribund tamoxifen-injected ptpn11fl/fl ert2-cre mice and ptpn11fl/fl littermate controls. Mice were injected with tamoxifen at 7 weeks of age and analysis was performed at 12 weeks of age. Top and middle panels are stained with H&E, and bottom panels are stained with Alcian blue to highlight cartilage. Scale bars: 1 mm in top panels, 500 μm in L4 vertebrae middle panels, and 200 μm in femora middle panels and all bottom panels. The amount of trabecular bone (t) is dramatically increased in ptpn11fl/fl ert2-cre vertebrae and femora. A region of remodeled (r) cortical bone (c) in femora of ptpn11fl/fl ert2-cre mice shows disorganized bone in this region compared with the same region in the control. Remains of ectopic cartilaginous elements (e) were identified in the trabecular bone region and ectopic cartilage formation (cf) was identified next to growth plates (g) in ptpn11fl/fl ert2-cre mice. The columnar formation of growth plates was disorganized in ptpn11fl/fl ert2-cre mice and the area of hypertrophic chondrocytes (hc) was elongated.

Mentions: Histological analysis confirmed that bones from tamoxifen-injected ptpn11fl/fl ert2-cre mice were osteopetrotic compared with littermate control mice (Fig. 5). Vertebrae and metaphyses of femora and humeri showed marked increases in the amount of trabecular bone (Fig. 5, top panels, and data not shown). Changes in the amount of cortical bone were less apparent. However, the uniform organization of remodeled cortical bone layers was clearly disrupted in SHP-2-deficient long bones, with regions of remodeled cortical bone showing ultrastructural features of trabecular bone (Fig. 5, right middle panels). Presumably, this trabecular-like cortical bone is formed after the time of tamoxifen administration.


Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations.

Bauler TJ, Kamiya N, Lapinski PE, Langewisch E, Mishina Y, Wilkinson JE, Feng GS, King PD - Dis Model Mech (2010)

Increased and disorganized bone and cartilage in induced SHP-2-deficient mice. Shown are representative images of L4 vertebrae and femora of moribund tamoxifen-injected ptpn11fl/fl ert2-cre mice and ptpn11fl/fl littermate controls. Mice were injected with tamoxifen at 7 weeks of age and analysis was performed at 12 weeks of age. Top and middle panels are stained with H&E, and bottom panels are stained with Alcian blue to highlight cartilage. Scale bars: 1 mm in top panels, 500 μm in L4 vertebrae middle panels, and 200 μm in femora middle panels and all bottom panels. The amount of trabecular bone (t) is dramatically increased in ptpn11fl/fl ert2-cre vertebrae and femora. A region of remodeled (r) cortical bone (c) in femora of ptpn11fl/fl ert2-cre mice shows disorganized bone in this region compared with the same region in the control. Remains of ectopic cartilaginous elements (e) were identified in the trabecular bone region and ectopic cartilage formation (cf) was identified next to growth plates (g) in ptpn11fl/fl ert2-cre mice. The columnar formation of growth plates was disorganized in ptpn11fl/fl ert2-cre mice and the area of hypertrophic chondrocytes (hc) was elongated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3046097&req=5

f5-0040228: Increased and disorganized bone and cartilage in induced SHP-2-deficient mice. Shown are representative images of L4 vertebrae and femora of moribund tamoxifen-injected ptpn11fl/fl ert2-cre mice and ptpn11fl/fl littermate controls. Mice were injected with tamoxifen at 7 weeks of age and analysis was performed at 12 weeks of age. Top and middle panels are stained with H&E, and bottom panels are stained with Alcian blue to highlight cartilage. Scale bars: 1 mm in top panels, 500 μm in L4 vertebrae middle panels, and 200 μm in femora middle panels and all bottom panels. The amount of trabecular bone (t) is dramatically increased in ptpn11fl/fl ert2-cre vertebrae and femora. A region of remodeled (r) cortical bone (c) in femora of ptpn11fl/fl ert2-cre mice shows disorganized bone in this region compared with the same region in the control. Remains of ectopic cartilaginous elements (e) were identified in the trabecular bone region and ectopic cartilage formation (cf) was identified next to growth plates (g) in ptpn11fl/fl ert2-cre mice. The columnar formation of growth plates was disorganized in ptpn11fl/fl ert2-cre mice and the area of hypertrophic chondrocytes (hc) was elongated.
Mentions: Histological analysis confirmed that bones from tamoxifen-injected ptpn11fl/fl ert2-cre mice were osteopetrotic compared with littermate control mice (Fig. 5). Vertebrae and metaphyses of femora and humeri showed marked increases in the amount of trabecular bone (Fig. 5, top panels, and data not shown). Changes in the amount of cortical bone were less apparent. However, the uniform organization of remodeled cortical bone layers was clearly disrupted in SHP-2-deficient long bones, with regions of remodeled cortical bone showing ultrastructural features of trabecular bone (Fig. 5, right middle panels). Presumably, this trabecular-like cortical bone is formed after the time of tamoxifen administration.

Bottom Line: Induced deletion of SHP-2 resulted in impaired hematopoiesis, weight loss and lethality.Skeletal malformations were associated with alterations in cartilage and a marked increase in trabecular bone mass.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620, USA.

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.

Show MeSH
Related in: MedlinePlus