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Macrophage-Derived TGF-β and VEGF Promote the Progression of Trauma-Induced Heterotopic Ossification

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Abstract

Heterotopic ossification (HO) is a pathological bone formation process caused by musculoskeletal trauma. HO is characterized by aberrant endochondral ossification and angiogenesis. Our previous studies have indicated that macrophage inflammation is involved in traumatic HO formation. In this study, we found that macrophage infiltration and TGF-β signaling activation are presented in human HO. Depletion of macrophages effectively suppressed traumatic HO formation in a HO mice model, and macrophage depletion significantly inhibited the activation of TGF-β/Smad2/3 signaling. In addition, the TGF-β blockade created by a neutralizing antibody impeded ectopic bone formation in vivo. Notably, endochondral ossification and angiogenesis are attenuated following macrophage depletion or TGF-β inhibition. Furthermore, our observations on macrophage polarization revealed that M2 macrophages, rather than M1 macrophages, play a critical role in supporting HO development by enhancing the osteogenic and chondrogenic differentiation of mesenchymal stem cells. Our findings on ectopic bone formation in HO patients and the mice model indicate that M2 macrophages are an important contributor for HO development, and that inhibition of M2 polarization or TGF-β activity may be a potential method of therapy for traumatic HO.

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DATA AVAILABILITY

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study is financially supported by the Science and Technology Commission of Shanghai Municipality (grant 19ZR1438900), the Key Project of National Natural Science Foundation of China (No.81830076), the Biomedical Technology Support Special Project of Shanghai “Science and Technology Innovation Action Plan” (No.20S31900300), the Shanghai Engineering Technology Research Center and Professional Technology Service Platform project of 2020 “Science and Technology Innovation Action Plan” of Shanghai(No.20DZ2254100), and the Shanghai ShenKang Hospital Development Center, Clinical Research Plan of SHDC (grant number: SHDC2020CR6019).

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  1. Bing Tu and Juehong Li contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai, 200233, China

    Bing Tu, Juehong Li, Ziyang Sun, Tongtong Zhang, Hang Liu, Feng Yuan & Cunyi Fan

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  1. Bing Tu
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Contributions

Bing Tu and Cunyi Fan designed the study; Feng Yuan collected the clinical samples; Bing Tu, Juehong Li, Ziyang Sun, TongTong Zhang, and Hang Liu performed the experiments and analyzed the data; Bing Tu and Feng Yuan evaluated the data and wrote the manuscript.

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Correspondence to Feng Yuan or Cunyi Fan.

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Tu, B., Li, J., Sun, Z. et al. Macrophage-Derived TGF-β and VEGF Promote the Progression of Trauma-Induced Heterotopic Ossification. Inflammation 46, 202–216 (2023). https://doi.org/10.1007/s10753-022-01723-z

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