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Nat Commun. 2018 Feb 7;9(1):551. doi: 10.1038/s41467-018-02988-5.

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

Author information

1
Department of Orthopedic Surgery, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA.
2
Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, 200030, Shanghai, China.
3
School of Dentistry, University of Michigan, Ann Arbor, MI, 48109, USA.
4
Department of Orthopedic Surgery, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA. xcao11@jhmi.edu.

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.

PMID:
29416028
PMCID:
PMC5803194
DOI:
10.1038/s41467-018-02988-5
[Indexed for MEDLINE]
Free PMC Article

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