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

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