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Bone Res. 2018 Apr 6;6:12. doi: 10.1038/s41413-018-0013-z. eCollection 2018.

SHP2 regulates skeletal cell fate by modifying SOX9 expression and transcriptional activity.

Author information

1
1Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, RI 02903 USA.
2
9Present Address: Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022 China.
3
2Orthopaedic Research Laboratories and Howard Hughes Medical Institute, Boston Children's Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02115 USA.
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3Division of Hematology and Oncology, Brown University Alpert Medical School and Rhode Island Hospital, Providence, RI 02903 USA.
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4Division of Rheumatology, Brown University Alpert Medical School and Rhode Island Hospital, Providence, RI 02903 USA.
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5Department of Pathology and Laboratory Medicine, University of Connecticut Health Center, Farmington, CT 06030 USA.
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6Department of Molecular and Cell Biology and Biochemistry, Brown University, 70 Ship Street, Providence, RI 02912 USA.
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7Department of Orthopedic Surgery, West China Hospital of Sichuan University, Chengdu, 610041 China.
9
8Laura and Issac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY 10016 USA.
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Contributed equally

Abstract

Chondrocytes and osteoblasts differentiate from a common mesenchymal precursor, the osteochondroprogenitor (OCP), and help build the vertebrate skeleton. The signaling pathways that control lineage commitment for OCPs are incompletely understood. We asked whether the ubiquitously expressed protein-tyrosine phosphatase SHP2 (encoded by Ptpn11) affects skeletal lineage commitment by conditionally deleting Ptpn11 in mouse limb and head mesenchyme using "Cre-loxP"-mediated gene excision. SHP2-deficient mice have increased cartilage mass and deficient ossification, suggesting that SHP2-deficient OCPs become chondrocytes and not osteoblasts. Consistent with these observations, the expression of the master chondrogenic transcription factor SOX9 and its target genes Acan, Col2a1, and Col10a1 were increased in SHP2-deficient chondrocytes, as revealed by gene expression arrays, qRT-PCR, in situ hybridization, and immunostaining. Mechanistic studies demonstrate that SHP2 regulates OCP fate determination via the phosphorylation and SUMOylation of SOX9, mediated at least in part via the PKA signaling pathway. Our data indicate that SHP2 is critical for skeletal cell lineage differentiation and could thus be a pharmacologic target for bone and cartilage regeneration.

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