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

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 Cao

doi:10.1038/s41467-018-02988-5

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

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 Cao

School of Medicine

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

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.

Original language	English (US)
Article number	551
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-02988-5
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "Inhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice",

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.",

author = "Xiao Wang and Fengfeng Li and Liang Xie and Janet Crane and Gehua Zhen and Yuji Mishina and Ruoxian Deng and Bo Gao and Hao Chen and Shen Liu and Ping Yang and Manman Gao and Manli Tu and Yiguo Wang and Mei Wan and Cunyi Fan and Xu Cao",

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AU - Wang, Xiao

AU - Li, Fengfeng

AU - Xie, Liang

AU - Crane, Janet

AU - Zhen, Gehua

AU - Mishina, Yuji

AU - Deng, Ruoxian

AU - Gao, Bo

AU - Chen, Hao

AU - Liu, Shen

AU - Yang, Ping

AU - Gao, Manman

AU - Tu, Manli

AU - Wang, Yiguo

AU - Wan, Mei

AU - Fan, Cunyi

AU - Cao, Xu

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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

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