{"doi":"10.1172/jci.insight.144925","title":"Macrophage TGF-β signaling is critical for wound healing with heterotopic ossification after trauma","abstract":"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.","journal":"JCI Insight","year":2022,"id":239107,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":51,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":690798,"name":"Johanna Nunez","orcid":"0000-0001-7017-2682","position":1,"is_corresponding":false},{"id":1226,"name":"Michael Sorkin","orcid":"0000-0002-7097-6135","position":2,"is_corresponding":false},{"id":295646,"name":"Simone Marini","orcid":"0000-0002-5704-3533","position":3,"is_corresponding":false},{"id":250811,"name":"Chase A. Pagani","orcid":"0000-0001-9834-2516","position":4,"is_corresponding":false},{"id":301494,"name":"Amy L. Strong","orcid":"0000-0002-2581-2481","position":5,"is_corresponding":false},{"id":250807,"name":"Charles Hwang","orcid":"0000-0002-3897-6813","position":6,"is_corresponding":false},{"id":241717,"name":"Shuli Li","orcid":"0000-0002-2335-507X","position":7,"is_corresponding":false},{"id":301491,"name":"Karthik Padmanabhan","orcid":"0000-0003-3405-7059","position":8,"is_corresponding":false},{"id":347353,"name":"Ravi Kumar","orcid":"0000-0003-0422-2818","position":9,"is_corresponding":false},{"id":864366,"name":"Alec C. Bancroft","orcid":"0000-0001-9505-4762","position":10,"is_corresponding":false},{"id":865212,"name":"Joey A. Greenstein","orcid":null,"position":11,"is_corresponding":false},{"id":301496,"name":"Reagan Nelson","orcid":"0000-0001-8543-6812","position":12,"is_corresponding":false},{"id":641942,"name":"Husain Rasheed","orcid":"0000-0003-0624-907X","position":13,"is_corresponding":false},{"id":690797,"name":"Nicholas Livingston","orcid":"0000-0002-1413-251X","position":14,"is_corresponding":false},{"id":253009,"name":"Kaetlin Vasquez","orcid":null,"position":15,"is_corresponding":false},{"id":250806,"name":"Amanda K. Huber","orcid":"0000-0003-0375-8709","position":16,"is_corresponding":false},{"id":231540,"name":"Benjamin Lévi","orcid":"0000-0001-8272-7139","position":17,"is_corresponding":false},{"id":250812,"name":"Nicole Patel","orcid":"0000-0003-2967-4167","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-19T00:22:36.865157Z","pmid":"36099022","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}