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

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