Targeting neutrophil extracellular traps: A novel strategy for treating heterotopic ossification

doi:10.5312/wjo.v16.i11.111242

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Nov 18, 2025 (publication date) through Nov 22, 2025

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World Journal of Orthopedics

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2218-5836

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Orthop. Nov 18, 2025; 16(11): 111242
Published online Nov 18, 2025. doi: 10.5312/wjo.v16.i11.111242

Targeting neutrophil extracellular traps: A novel strategy for treating heterotopic ossification

Chen-Yu Song, Hong-Ping Yu, Fei-Yan Mu, Jing-Shun Lu, Min Yang, Meng-Han Chang, Kai-Yang Wang

Chen-Yu Song, Kai-Yang Wang, Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China

Hong-Ping Yu, Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, Xiamen 361000, Fujian Province, China

Fei-Yan Mu, Southern Central Hospital of Yunnan Province, The First People’s Hospital of Honghe State, Honghe Hani and Yi Autonomous Prefecture Mengzi 661100, Yunnan Province, China

Jing-Shun Lu, Department of Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu 241000, Anhui Province, China

Min Yang, Department of Traditional Chinese Medicine, Meilong Community Health Service Center of Minhang District, Shanghai 200233, China

Meng-Han Chang, Department of Orthopedic Surgery, Jinling Hospital, Affliated Hospital of Medical School, Nanjing University, Nanjing 210002, Jiangsu Province, China

Co-first authors: Chen-Yu Song and Hong-Ping Yu.

Author contributions: Song CY and Yu HP wrote and edited the manuscript, they contributed equally to this article, they are the co-first authors of this manuscript; Mu FY, Lu JS, Yang M, Chang MH, and Wang KY contributed to review; Lu JS and Yang M contributed to edit; Wang KY conceived and revised this paper; and all authors thoroughly reviewed and endorsed the final manuscript.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Corresponding author: Kai-Yang Wang, MD, Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai 200233, China. ortho_wang@163.com

Received: June 27, 2025
Revised: August 10, 2025
Accepted: October 20, 2025
Published online: November 18, 2025
Processing time: 140 Days and 23.4 Hours

Abstract

In this article, we make a comment on the recent article by Sun et al, focusing on the advances of neutrophil extracellular traps (NETs) formation in common osteoarticular diseases. Neutrophils are the first line to eliminate invading pathogens including fungal and bacterial infections via releasing hydrolytic enzymes and reactive oxygen species. Besides, neutrophils will accumulate at the inflammatory site and release NETs, which are composed of histones, DNA and granular proteins. Traumatic heterotopic ossification (THO) was generally believed to develop through four stages: Inflammation, chondrogenesis, osteogenesis, and bone maturation. Thus, it can be seen that THO was related to inflammation and bone formation. Apart from immune and infectious diseases, recent studies have also shown that NETs play a significant role in the pathogenesis of THO. This article focuses on elaborating the role of NETs in the onset of THO, discussing the existing problems in the current research and outlining future directions.

Keywords: Neutrophil; Neutrophil extracellular traps; Heterotopic ossification; Molecular mechanisms; Therapeutic strategy; Research progress

Core Tip: The role of neutrophils and neutrophil extracellular traps (NETs) in the pathogenesis of heterotopic ossification (HO) has been extensively studied. Neutrophils accelerate the progression of HO through multiple molecular mechanisms, including upregulating the expression levels of bone morphogenetic protein, interleukin-1α and transforming growth factor β, leading to osteogenic differentiation of mesenchymal stem cells. Meanwhile, the presence of NETs causes the local area to remain in persistent inflammation, which provides a suitable microenvironment for bone formation. By transplanting umbilical cord mesenchymal stem cells and applying batroxobin, QBM076, necrosulfonamide and peptidylarginine deaminase 4 to target neutrophils or NETs, which can play a positive role in the treatment of HO. The therapeutic potential of NETs for addressing HO warrants further investigation in future studies.