Key Takeaways & Executive Findings
- ā¢ā¢ Macrophage depletion reduces neurogenic heterotopic ossification volume by approximately 90%. ā¢ Fibro-adipogenic progenitor pathological reprogramming is driven by substance P, calcitonin gene-related peptide, oncostatin M/JAK/STAT, IL-1Ī², and lipopolysaccharide. ā¢ Hypoxia-angiogenesis signaling via HIF-1Ī±/VEGF is a critical mechanism. ā¢ Animal models include spinal cord injury (cardiotoxin, denervation, tendon injury, lipopolysaccharide) and traumatic brain injury (free fall, controlled cortical impact, fluid percussion plus peripheral trauma).
Abstract
BACKGROUND: Neurogenic heterotopic ossification frequently occurs within 1 to 3 months following spinal cord injury or traumatic brain injury, characterized by abnormal bone formation in periarticular soft tissues. The precise pathogenesis remains unclear, underscoring the urgent need for systematic research to inform clinical management. OBJECTIVE: To summarize recent advances in animal models of neurogenic heterotopic ossification and elucidate its underlying mechanisms, with a particular focus on the pathological differentiation of osteogenic precursor cells, remodeling of the local tissue microenvironment, and the interplay between neural regulation and neurogenic heterotopic ossification formation. METHODS: PubMed, CNKI, and SinoMed were searched from inception to January 2025. Chinese search terms included 'neurogenic heterotopic ossification, spinal cord injury, traumatic brain injury, heterotopic ossification'; English search terms included 'Neurogenic Heterotopic Ossification, spinal cord injury, Traumatic brain injury, ossification, heterotopic, Central nervous system'. Literature related to animal models and mechanisms of neurogenic heterotopic ossification was included to summarize key pathogenic processes. RESULTS AND CONCLUSION: The recruitment and aberrant osteogenic differentiation of osteogenic precursor cells (mainly fibro-adipogenic progenitors) are regulated by local microenvironmental factors such as hypoxia, inflammation, and angiogenesis. Neurotrophic factors, calcitonin gene-related peptide, and substance P promote aberrant ossification through neuro-immune interactions. Future research should construct a systematic molecular map, explore core signaling pathways, and develop novel targeted interventions to achieve early identification and individualized treatment of neurogenic heterotopic ossification, thereby improving patient outcomes.
1. Introduction
Neurogenic heterotopic ossification (NHO) is a severe complication following central nervous system injury, characterized by pathological bone formation in soft tissues outside the skeletal system, such as muscles, fascia, or ligaments [1-2]. NHO typically forms within 3 months after injury, significantly restricting joint range of motion and potentially encasing neurovascular bundles, leading to severe pain, nerve compression, and ultimately hindering patient rehabilitation and reducing quality of life [2-3].
Research on the mechanisms of NHO has long been constrained by two major bottlenecks: first, the lack of specific and sensitive early biomarkers; conventional imaging (X-ray, CT) can only detect mature ossification, while serum markers (alkaline phosphatase, C-reactive protein) are associated with inflammation but lack neurogenic specificity for early precise warning [4]. Second, NHO involves multi-level interactions among 'neural signals, immune microenvironment, and bone metabolism', and traditional animal models cannot fully simulate the complex pathology after human central nervous system injury. For example, simple muscle injury models cannot reproduce autonomic dysregulation and persistent inflammation after spinal cord injury, while traumatic heterotopic ossification models overlook the driving role of neurogenic factors [5-6].
By integrating research advances in NHO animal models with multi-omics analysis techniques, combined with clinical cohort data and basic research findings, this review focuses on three core mechanismsāpathological differentiation of osteogenic precursor cells, remodeling of the hypoxic/inflammatory microenvironment, and regulatory networks of neural factors (e.g., nerve growth factor, calcitonin gene-related peptide)āto systematically analyze the pathogenesis of NHO, aiming to provide a theoretical basis for precise prevention and treatment, and to envision future research directions.
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Ren Qingsong, Xie Yulei, Liu Jingjing, Lin Jingyi, Long Danlei, Zhang Chunyu, Xie Liang, Zheng Kaiyuan, Wang Yinxu (2026). Animal models of neurogenic heterotopic ossification: key disease progression and pathogenesis. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21299
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Frequently Asked Questions
What is neurogenic heterotopic ossification (NHO)?
NHO is a pathological condition where bone forms abnormally in soft tissues (e.g., muscles, fascia, ligaments) after central nervous system injury, typically appearing within 1-3 months, most commonly around the hip joint. It can cause pain, nerve compression, and restricted joint movement.
What are the key mechanisms of NHO?
Key mechanisms include aberrant differentiation of osteogenic precursor cells (mainly fibro-adipogenic progenitors) driven by local hypoxia, inflammation, and angiogenesis; neuro-immune interactions involving factors like substance P and calcitonin gene-related peptide; and signaling pathways such as HIF-1Ī±/VEGF and oncostatin M/JAK/STAT.
Which animal models are used to study NHO?
Animal models include spinal cord injury models (e.g., cardiotoxin injection, denervation, tendon injury, lipopolysaccharide) and traumatic brain injury models (e.g., free fall, controlled cortical impact, fluid percussion plus peripheral trauma). These models aim to replicate the neurogenic environment.
What are the clinical challenges in NHO management?
Challenges include lack of early biomarkers, delayed diagnosis, limited efficacy of nonsteroidal anti-inflammatory drugs (about one-third of patients do not respond), and high recurrence rates after surgery (19.8%-50%). Risk factors include young age, male sex, severe injury, ACVR1 R206H mutation, delayed rehabilitation, spasticity, and pressure ulcers.
What future research directions are suggested?
Future research should focus on constructing a systematic molecular map of NHO, exploring core signaling pathways, and developing targeted interventions for early detection and individualized treatment, ultimately improving patient outcomes.
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