Activation of Hedgehog signaling in mesenchymal stem cells induces cartilage and bone tumor formation via Wnt/β-Catenin

  1. Qi Deng
  2. Ping Li
  3. Manju Che
  4. Jiajia Liu
  5. Soma Biswas
  6. Gang Ma
  7. Lin He
  8. Zhanying Wei
  9. Zhenlin Zhang
  10. Yingzi Yang
  11. Huijuan Liu  Is a corresponding author
  12. Baojie Li  Is a corresponding author
  1. Shanghai Jiao Tong University, China
  2. Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China
  3. Harvard School of Dental Medicine, United States

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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

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. Soma Biswas

    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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1427-2678
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Yingzi Yang

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3933-887X
  11. 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.
  12. Baojie Li

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    For correspondence
    libj@sjtu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3913-1062

Funding

National Natural Science Foundation of China (81373210)

  • Baojie Li

National Natural Science Foundation of China (81520108012)

  • Baojie Li

National Natural Science Foundation of China (91542120)

  • Baojie Li

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

  • Baojie Li

Schaefer Research Scholarship

  • Baojie Li

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)
  4. Version of Record published: September 27, 2019 (version 2)

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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  1. Qi Deng
  2. Ping Li
  3. Manju Che
  4. Jiajia Liu
  5. Soma Biswas
  6. Gang Ma
  7. Lin He
  8. Zhanying Wei
  9. Zhenlin Zhang
  10. Yingzi Yang
  11. Huijuan Liu
  12. Baojie Li
(2019)
Activation of Hedgehog signaling in mesenchymal stem cells induces cartilage and bone tumor formation via Wnt/β-Catenin
eLife 8:e50208.
https://doi.org/10.7554/eLife.50208

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