Inhibition of overactive TGF-? 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-? 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-? that recruit mesenchymal stromal/progenitor cells (MSPCs) in the HO microenvironment. Transgenic expression of active TGF-? in tendon induces spontaneous HO, whereas systemic injection of a TGF-? 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-? type II receptor in MSPCs inhibits HO progression in HO mouse models. Our study points toward elevated levels of active TGF-? as inducers and promoters of ectopic bone formation, and suggest that TGF-? might be a therapeutic target in HO.

SUBMITTER: Wang X 

PROVIDER: S-EPMC5803194 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature