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

查看全文 作　　者：Chunlin [1,9]Zuo;Lijun [1]Wang;Raghavendra [1]M.Kamalesh;Margot [2]E.Bowen;Douglas [1]C.Moore;Mark [3]S.Dooner;Anthony [4]M.Reginato;Qian [5]Wu;Christoph [6]Schorl;Yueming [7]Song;Matthew [2]L.Warman;Benjamin [8]G.Neel;Michael [1]G.Ehrlich;Wentian [1]Yang

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

出　　处：《Bone Research》索引2018年第6卷第2期,共13页

基　　金：supported by NIH R21AR57156;NIH R37 CA49152;the Rhode Island Hospital Orthopaedic Foundation;grant from the Pediatric Orthopaedic Society of North America;Arthritis National Research Foundation;recipient of Ryan Fellowship;pilot award recipient from NIGMS1P20 GM119943 摘　　要：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-lox P'-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, q RT-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. 关键词：SOX9 骨胳房间调整基因表达式修改 RT-PCR 造骨细胞

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

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