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shp2 regulates skeletal cell fate by modifying SOX9 expression and transcriptional activity

Bone Research 2018年第2期6卷 132-144页

作者： Chunlin Zuo Lijun Wang Raghavendra M.Kamalesh Margot E.Bowen Douglas C.Moore Mark S.Dooner Anthony M.Reginato Qian Wu Christoph Schorl Yueming Song Matthew L.Warman Benjamin G.Neel Michael G.Ehrlich Wentian Yang Department of Orthopaedics Brown University Alpert Medical School and Rhode Island HospitalProvidenceRI 02903USA Orthopaedic Research Laboratories and Howard Hughes Medical Institute Boston Children's Hospital and Department of GeneticsHarvard Medical SchoolBostonMA 02115USA Division of Hematology and Oncology Brown University Alpert Medical School and Rhode Island HospitalProvidenceRI 02903USA Division of Rheumatology Brown University Alpert Medical School and Rhode Island HospitalProvidenceRI 02903USA Department of Pathology and Laboratory Medicine University of Connecticut Health CenterFarmingtonCT 06030USA Department of Molecular and cell Biology and Biochemistry Brown University70 Ship StreetProvidenceRI 02912USA Department of Orthopedic Surgery West China Hospital of Sichuan UniversityChengdu 610041 Laura and Issac Perlmutter Cancer Center NYU Langone Medical CenterNew YourkNY 10016USA Department of Endocrinology the First Affiliated Hospital of Anhui Medical UniversityHefei 230022China

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 ***2-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： shp2 regulates skeletal cell modifying SOX9 expression transcriptional activity SOX

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