Activering van Hedgehog-signalering in mesenchymale stamcellen induceert kraakbeen en bottumorvorming via Wnt / β-Catenin

september 6, 2019 0 Door admin

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Abstract

Indian Hedgehog (IHH) signaling, a key regulator of skeletal development, is highly activated in cartilage and bone tumors. Yet deletion of Ptch1, encoding an inhibitor of IHH receptor Smoothened (SMO), in chondrocyte or osteoblasts does not cause tumorigenesis. Here, we show that Ptch1 deletion in mice Prrx1 mesenchymal stem/stromal cells (MSCs) promotes MSC proliferation and osteogenic and chondrogenic differentiation but inhibits adipogenic differentiation. Moreover, Ptch1 deletion led to development of osteoarthritis-like phenotypes, exostoses, enchondroma, and osteosarcoma in Smo-Gli1/2-dependent manners. The cartilage and bone tumors are originated from Prrx1 lineage cells and express low levels of osteoblast and chondrocyte markers, respectively. Mechanistically, Ptch1 deletion increases the expression of Wnt5a/6 and leads to enhanced b-Catenin activation. Inhibiting Wnt/b-Catenin pathway suppresses development of skeletal anomalies including enchondroma and osteosarcoma. These findings suggest that cartilage/bone tumors arise from their early progenitor cells and identify the Wnt/b-Catenin pathway as a pharmacological target for cartilage/bone neoplasms.

Article and author information

Author details

  1. Qi Deng

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests

    The authors declare that no competing interests exist.

  2. Ping Li

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests

    The authors declare that no competing interests exist.

  3. Manju Che

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests

    The authors declare that no competing interests exist.

  4. Jiajia Liu

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests

    The authors declare that no competing interests exist.

  5. Gang Ma

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests

    The authors declare that no competing interests exist.

  6. Lin He

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests

    The authors declare that no competing interests exist.

  7. Zhanying Wei

    Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
    Competing interests

    The authors declare that no competing interests exist.

  8. Zhenlin Zhang

    Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
    Competing interests

    The authors declare that no competing interests exist.

  9. Huijuan Liu

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    For correspondence

    liuhj@sjtu.edu.cn

    Competing interests

    The authors declare that no competing interests exist.

Funding

National Natural Science Foundation of China (81373210)

National Natural Science Foundation of China (81520108012)

National Natural Science Foundation of China (91542120)

National Key Research and Development Program of China (2017YFA0103602)

Schaefer Research Scholarship

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse work was carried out following the recommendations from the NationalResearch Council Guide for the Care and Use of Laboratory Animals, with the protocols approved by the Institutional Animal Care and Use Committee of Shanghai, China [SYXK (SH) 2011-0112]. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Marianne E Bronner, California Institute of Technology, United States

Publication history

  1. Received: July 15, 2019
  2. Accepted: August 31, 2019
  3. Accepted Manuscript published: September 4, 2019 (version 1)

Copyright

© 2019, Deng et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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