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

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

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

  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

  • Antibodies, Neutralizing
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Becaplermin
  • Receptor, Transforming Growth Factor-beta Type II