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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Article number551
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Heterotopic Ossification
osteogenesis
progressions
mice
Bone
Mesenchymal Stromal Cells
tendons
pathogenesis
cartilage
Osteogenesis
Tendons
Cartilage
Neutralizing Antibodies
cells
antibodies
bones
injection
Osteoclasts

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Inhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice. / Wang, Xiao; Li, Fengfeng; Xie, Liang; Crane, Janet; Zhen, Gehua; Mishina, Yuji; Deng, Ruoxian; Gao, Bo; Chen, Hao; Liu, Shen; Yang, Ping; Gao, Manman; Tu, Manli; Wang, Yiguo; Wan, Mei; Fan, Cunyi; Cao, Xu.

In: Nature Communications, Vol. 9, No. 1, 551, 01.12.2018.

Research output: Contribution to journalArticle

Wang, X, Li, F, Xie, L, Crane, J, Zhen, G, Mishina, Y, Deng, R, Gao, B, Chen, H, Liu, S, Yang, P, Gao, M, Tu, M, Wang, Y, Wan, M, Fan, C & Cao, X 2018, 'Inhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice', Nature Communications, vol. 9, no. 1, 551. https://doi.org/10.1038/s41467-018-02988-5
Wang, Xiao ; Li, Fengfeng ; Xie, Liang ; Crane, Janet ; Zhen, Gehua ; Mishina, Yuji ; Deng, Ruoxian ; Gao, Bo ; Chen, Hao ; Liu, Shen ; Yang, Ping ; Gao, Manman ; Tu, Manli ; Wang, Yiguo ; Wan, Mei ; Fan, Cunyi ; Cao, Xu. / Inhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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