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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Achilles Tendon / drug effects
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Achilles Tendon / injuries
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Adult
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Animals
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Antibodies, Neutralizing / pharmacology
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Becaplermin / metabolism
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Bone Remodeling
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Brain Injuries, Traumatic
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Cartilage
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Case-Control Studies
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Disease Models, Animal
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Elbow Injuries
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Elbow Joint / surgery
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Female
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Fracture Fixation, Internal
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Fractures, Bone
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Humans
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Male
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Mesenchymal Stem Cells / metabolism
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Mice
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Mice, Knockout
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Mice, Transgenic
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Middle Aged
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Muscle, Skeletal / pathology
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Myositis Ossificans / metabolism
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Ossification, Heterotopic / metabolism*
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Osteoclasts*
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Osteogenesis / drug effects
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Receptor, Transforming Growth Factor-beta Type II / genetics
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Spinal Cord Injuries
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Tendon Injuries
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Tendons
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta1 / metabolism
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Young Adult
Substances
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Antibodies, Neutralizing
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TGFB1 protein, human
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Becaplermin
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Receptor, Transforming Growth Factor-beta Type II