{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:27:59Z","timestamp":1791419279314,"version":"4.3.3"},"reference-count":169,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/ National Institute of Arthritis and Musculoskeletal and Skin Diseases","award":["1K08AR084614-01A1"],"award-info":[{"award-number":["1K08AR084614-01A1"]}]},{"award":["1K08AR084614-01A1"],"award-info":[{"award-number":["1K08AR084614-01A1"]}],"id":[{"id":"https:\/\/ror.org\/006zn3t30","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Trauma-induced heterotopic ossification (tHO) is characterized by aberrant ectopic bone formation in soft tissue following high-energy trauma, affecting &gt;60% of combat-related amputees and &gt;50% of major burn patients. Current prophylactic strategies (including NSAIDs, bisphosphonates, and low-dose radiation) lack mechanistic specificity, carry significant side effects, and surgical excision carries a 27% recurrence rate. This review reframes tHO pathogenesis through the neural\u2013immune axis, arguing that ectopic bone formation is a downstream consequence of dysregulated neuroimmune signaling rather than a primary osteogenic event. Following trauma, nociceptor activation drives nociception-induced neural inflammation (NINI), releasing substance P (SP) and calcitonin gene-related peptide (CGRP), which disrupts the blood\u2013nerve barrier, mobilizes neural crest-derived progenitor cells, and, alongside BMP-2\/SMAD1\/5\/8 signaling and M1-polarized macrophage activation, establishes a permissive osteogenic microenvironment. A BMP-2\/CGRP positive feedback loop sustains aberrant osteogenesis, converging on osteogenic transcription factors Runx2, SOX5\/6\/9, and Osterix. Dysregulated noncoding RNAs represent promising pre-radiographic biomarkers. This neural\u2013immune framework motivates mechanism-based therapeutic strategies targeting CGRP (fremanezumab, erenumab), SP\/NK1 signaling (aprepitant), and macrophage polarization (metformin, palovarotene, rapamycin), with multi-node combination approaches tailored to the temporal stages of tHO offering the most promise for precision prophylaxis.<\/jats:p>","DOI":"10.3390\/cells15090827","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T10:15:27Z","timestamp":1777630527000},"page":"827","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neuro-Immune Axis in Trauma-Induced Heterotopic Ossification: Mechanisms and Therapeutic Implications"],"prefix":"10.3390","volume":"15","author":[{"given":"Oluomachukwu Jennifer","family":"Agu","sequence":"first","affiliation":[{"name":"Department of Surgery, University of California Davis Medical Center, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifford","family":"Pereira","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California Davis Medical Center, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9955-0591","authenticated-orcid":false,"given":"Ishaan","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California Davis Medical Center, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Moran","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California Davis Medical Center, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4126-7102","authenticated-orcid":false,"given":"Tahmineh","family":"Mokhtari","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California Davis Medical Center, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"ref_1","first-page":"353","article-title":"Heterotopic ossification as a complication of iliac crest bone harvesting in a case of implant therapy","volume":"24","author":"Kourkouta","year":"2009","journal-title":"Int. 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