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Publication : SHP2 Regulates the Osteogenic Fate of Growth Plate Hypertrophic Chondrocytes.

First Author  Wang L Year  2017
Journal  Sci Rep Volume  7
Issue  1 Pages  12699
PubMed ID  28983104 Mgi Jnum  J:255705
Mgi Id  MGI:6109408 Doi  10.1038/s41598-017-12767-9
Citation  Wang L, et al. (2017) SHP2 Regulates the Osteogenic Fate of Growth Plate Hypertrophic Chondrocytes. Sci Rep 7(1):12699
abstractText  Transdifferentiation of hypertrophic chondrocytes into bone-forming osteoblasts has been reported, yet the underlying molecular mechanism remains incompletely understood. SHP2 is an ubiquitously expressed cytoplasmic protein tyrosine phosphatase. SHP2 loss-of-function mutations in chondroid cells are linked to metachondromatosis in humans and mice, suggesting a crucial role for SHP2 in the skeleton. However, the specific role of SHP2 in skeletal cells has not been elucidated. To approach this question, we ablated SHP2 in collagen 2alpha1(Col2alpha1)-Cre- and collagen 10alpha1(Col10alpha1)-Cre-expressing cells, predominantly proliferating and hypertrophic chondrocytes, using "Cre-loxP"-mediated gene excision. Mice lacking SHP2 in Col2alpha1-Cre-expressing cells die at mid-gestation. Postnatal SHP2 ablation in the same cell population caused dwarfism, chondrodysplasia and exostoses. In contrast, mice in which SHP2 was ablated in the Col10alpha1-Cre-expressing cells appeared normal but were osteopenic. Further mechanistic studies revealed that SHP2 exerted its influence partly by regulating the abundance of SOX9 in chondrocytes. Elevated and sustained SOX9 in SHP2-deficient hypertrophic chondrocytes impaired their differentiation to osteoblasts and impaired endochondral ossification. Our study uncovered an important role of SHP2 in bone development and cartilage homeostasis by influencing the osteogenic differentiation of hypertrophic chondrocytes and provided insight into the pathogenesis and potential treatment of skeletal diseases, such as osteopenia and osteoporosis.
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