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Inhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice

Author

Listed:
  • Xiao Wang

    (Johns Hopkins University)

  • Fengfeng Li

    (Shanghai Sixth People’s Hospital)

  • Liang Xie

    (Johns Hopkins University)

  • Janet Crane

    (Johns Hopkins University)

  • Gehua Zhen

    (Johns Hopkins University)

  • Yuji Mishina

    (University of Michigan)

  • Ruoxian Deng

    (Johns Hopkins University)

  • Bo Gao

    (Johns Hopkins University)

  • Hao Chen

    (Johns Hopkins University)

  • Shen Liu

    (Johns Hopkins University
    Shanghai Sixth People’s Hospital)

  • Ping Yang

    (Johns Hopkins University)

  • Manman Gao

    (Johns Hopkins University)

  • Manli Tu

    (Johns Hopkins University)

  • Yiguo Wang

    (Johns Hopkins University)

  • Mei Wan

    (Johns Hopkins University)

  • Cunyi Fan

    (Shanghai Sixth People’s Hospital)

  • Xu Cao

    (Johns Hopkins University)

Abstract

Acquired heterotopic ossification (HO) is a painful and debilitating disease characterized by extraskeletal bone formation after injury. The exact pathogenesis of HO remains unknown. Here we show that TGF-β initiates and promotes HO in mice. We find that calcified cartilage and newly formed bone resorb osteoclasts after onset of HO, which leads to high levels of active TGF-β that recruit mesenchymal stromal/progenitor cells (MSPCs) in the HO microenvironment. Transgenic expression of active TGF-β in tendon induces spontaneous HO, whereas systemic injection of a TGF-β neutralizing antibody attenuates ectopic bone formation in traumatic and BMP-induced mouse HO models, and in a fibrodysplasia ossificans progressive mouse model. Moreover, inducible knockout of the TGF-β type II receptor in MSPCs inhibits HO progression in HO mouse models. Our study points toward elevated levels of active TGF-β as inducers and promoters of ectopic bone formation, and suggest that TGF-β might be a therapeutic target in HO.

Suggested Citation

  • Xiao Wang & Fengfeng Li & Liang Xie & Janet Crane & Gehua Zhen & Yuji Mishina & Ruoxian Deng & Bo Gao & Hao Chen & Shen Liu & Ping Yang & Manman Gao & Manli Tu & Yiguo Wang & Mei Wan & Cunyi Fan & Xu , 2018. "Inhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-02988-5
    DOI: 10.1038/s41467-018-02988-5
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