Inhibition of overactive TGF-\u03b2 attenuates progression of heterotopic ossification in mice

Xiao Wang,Bo Gao,Janet Crane,Gehua Zhen,Ruoxian Deng,Ping Yang,Xu Cao,Yiguo Wang,Shen Liu,Mei Wan,Manli Tu,Cunyi Fan,Liang Xie,Fengfeng Li,Hao Chen,Yuji Mishina,Manman Gao

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.

Highlights

Acquired heterotopic ossification (HO) is a painful and debilitating disease characterized by extraskeletal bone formation after injury
We have previously demonstrated that PDGF-BB secreted by tartrate-resistant acid phosphatase-positive (TRAP+) preosteoclasts recruits endothelial progenitors and mesenchymal stromal/progenitor cells (MSPCs) to couple CD31highEmcnhigh blood vessels with osteogenesis[26,27,28]
Elevated levels of active TGF-β1 and PDGF-BB in serum were seen in the osteogenesis stage HO patients relative to the maturation stage, both of which were a higher concentration than healthy controls (Fig. 1i, j)

Summary

Introduction

Acquired heterotopic ossification (HO) is a painful and debilitating disease characterized by extraskeletal bone formation after injury. Elevated levels of active TGF-β1 and PDGF-BB in serum were seen in the osteogenesis stage HO patients relative to the maturation stage, both of which were a higher concentration than healthy controls (Fig. 1i, j).

Results

Conclusion