Macrophage TGF-β signaling is critical for wound healing with heterotopic ossification after trauma

JCI Insight. 2022 Oct 24;7(20):e144925. doi: 10.1172/jci.insight.144925.


Transforming growth factor-β1 (TGF-β1) plays a central role in normal and aberrant wound healing, but the precise mechanism in the local environment remains elusive. Here, using a mouse model of aberrant wound healing resulting in heterotopic ossification (HO) after traumatic injury, we find autocrine TGF-β1 signaling in macrophages, and not mesenchymal stem/progenitor cells, is critical in HO formation. In-depth single-cell transcriptomic and epigenomic analyses in combination with immunostaining of cells from the injury site demonstrated increased TGF-β1 signaling in early infiltrating macrophages, with open chromatin regions in TGF-β1-stimulated genes at binding sites specific for transcription factors of activated TGF-β1 (SMAD2/3). Genetic deletion of TGF-β1 receptor type 1 (Tgfbr1; Alk5), in macrophages, resulted in increased HO, with a trend toward decreased tendinous HO. To bypass the effect seen by altering the receptor, we administered a systemic treatment with TGF-β1/3 ligand trap TGF-βRII-Fc, which resulted in decreased HO formation and a delay in macrophage infiltration to the injury site. Overall, our data support the role of the TGF-β1/ALK5 signaling pathway in HO.

Keywords: Bone Biology; Growth factors; Immunology; Macrophages.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Chromatin / metabolism
  • Humans
  • Ligands
  • Macrophages / metabolism
  • Ossification, Heterotopic* / metabolism
  • Receptor, Transforming Growth Factor-beta Type I / genetics
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1* / metabolism
  • Wound Healing


  • Chromatin
  • Ligands
  • Receptor, Transforming Growth Factor-beta Type I
  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta