Palee Suwannika, Jarusriwanna Atthakorn, Lee Danielle, Yener Ugur, Kaye Alan D, Shaparin Naum, Wahezi Sayed E
Department of Rehabilitation Medicine, Faculty of Medicine, Naresuan University, Phitsanulok, Thailand.
Department of Orthopaedics, Faculty of Medicine, Naresuan University, Phitsanulok, Thailand.
Pain Physician. 2025 Jul;28(4):287-297.
This scoping review systematically evaluates and synthesizes evidence on the presence of neoinnervation in chronic tendon pain. By analyzing the frequency and progression of neural biomarker upregulation, the present investigation seeks to illuminate existing knowledge gaps, contextualize shifts in research focus over time, and propose potential therapeutic approaches for the more precise and effective management of tendinopathy.
To identify major neural biomarkers associated with nerve ingrowth, detailing historical development, current understanding, and implications in tendinopathy.
A scoping review.
An academic medical center.
Searches were conducted up to June 2024 using PubMed, Embase, Web of Science, and Scopus, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. The selected studies included clinical human case-control studies and in vivo experimental animal models that examined neoinnervation in tendinopathy. Data extraction included study design, animal induction models, biomarker detection methods, neural biomarker upregulation, and supporting evidence to evaluate the involvement of neoinnervation and the role of the paratenon in tendinopathy.
Of the 26 studies reviewed, 19 (73%) identified neoinnervation in chronic tendinopathy, and 20 (76.9%) highlighted the role of the paratenon, suggesting its potential as a key target for therapeutic interventions. Notably, 14 studies (53.8%) examined both neoinnervation and the paratenon's role, indicating significant interplay. Analyses of neural biomarkers revealed possible upregulation of protein gene product 9.5 (PGP 9.5) in 15 studies (57.6%) and substance P in 13 studies (50%), emphasizing the crucial roles of those biomarkers in the neurobiological mechanisms of tendinopathy pain. Other biomarkers, including calcitonin gene-related peptide (CGRP), tyrosine hydroxylase, growth-associated protein-43 (GAP-43), NMDA receptor (NMDAR), glutamate, neurokinin 1 receptor (NK1R), neuropeptide Y, adrenoreceptor, nerve sprouting markers, specific chemokines, and various immune-related markers, were also identified as potentially upregulated. Our review of temporal trends indicates that recent research has expanded to encompass a broader range of biomarkers, thereby enhancing our understanding of the complexity and multisystem involvement in the pathology of tendinopathy.
This review is limited by the predominance of case-control and experimental studies, which inherently offer lower levels of evidence due to methodological constraints like lack of randomization and potential biases. Additionally, the present review may not fully address how biomarker expression or neoinnervation changes over disease stages or treatment, the comprehension of which is critical for understanding progression and management.
The present investigation highlights the critical role of neoinnervation and the paratenon in chronic tendinopathy, with a significant overlap suggesting interrelated roles in the condition. This finding emphasizes the need to incorporate neurobiological pathways into therapeutic strategies. The evolution of neural biomarker studies reveals a complex interplay in pain mechanisms, underscoring the potential for targeting specific nerve ingrowth pathways within the paratenon to enhance treatment efficacy. Future research should aim to elucidate the therapeutic potential of targeting specific paratenon nerve ingrowth pathways, which could improve the efficacy of treatments for chronic tendon pain substantially.
本综述系统地评估和综合了关于慢性肌腱疼痛中新生神经支配存在的证据。通过分析神经生物标志物上调的频率和进展情况，本研究旨在阐明现有知识空白，梳理研究重点随时间的变化情况，并提出更精确、有效的肌腱病治疗方法。
确定与神经长入相关的主要神经生物标志物，详述其历史发展、当前认识以及在肌腱病中的意义。
一项综述。
一所学术医疗中心。
截至2024年6月，使用PubMed、Embase、Web of Science和Scopus进行检索，遵循系统评价和Meta分析扩展版的系统评价优先报告条目（PRISMA-ScR）指南。所选研究包括临床人体病例对照研究和体内实验动物模型，这些研究检测了肌腱病中的新生神经支配。数据提取包括研究设计、动物诱导模型、生物标志物检测方法、神经生物标志物上调情况以及支持评估新生神经支配的参与情况和腱旁组织在肌腱病中的作用的证据。
在纳入综述的26项研究中，19项（73%）在慢性肌腱病中发现了新生神经支配，20项（76.9%）强调了腱旁组织的作用，表明其作为治疗干预关键靶点的潜力。值得注意的是，14项研究（53.8%）同时研究了新生神经支配和腱旁组织的作用，表明存在显著的相互作用。对神经生物标志物的分析显示，15项研究（57.6%）中蛋白基因产物9.5（PGP 9.5）可能上调，13项研究（50%）中P物质可能上调，强调了这些生物标志物在肌腱病疼痛神经生物学机制中的关键作用。其他生物标志物，包括降钙素基因相关肽（CGRP）、酪氨酸羟化酶、生长相关蛋白43（GAP-43）、N-甲基-D-天冬氨酸受体（NMDAR）、谷氨酸、神经激肽1受体（NK1R）、神经肽Y、肾上腺素能受体、神经发芽标志物、特定趋化因子以及各种免疫相关标志物，也被确定为可能上调。我们对时间趋势的综述表明，最近的研究已扩展到涵盖更广泛的生物标志物，从而增强了我们对肌腱病病理复杂性和多系统参与情况的理解。
本综述受到病例对照研究和实验研究占主导的限制，由于缺乏随机化和潜在偏倚等方法学限制，这些研究本质上提供的证据水平较低。此外，本综述可能未充分探讨生物标志物表达或新生神经支配如何随疾病阶段或治疗而变化，而理解这一点对于了解疾病进展和管理至关重要。
本研究强调了新生神经支配和腱旁组织在慢性肌腱病中的关键作用，两者存在显著重叠表明在该病症中具有相互关联的作用。这一发现强调了将神经生物学途径纳入治疗策略的必要性。神经生物标志物研究的演变揭示了疼痛机制中的复杂相互作用，强调了针对腱旁组织内特定神经长入途径以提高治疗效果的潜力。未来的研究应旨在阐明针对特定腱旁组织神经长入途径的治疗潜力，这可能会大幅提高慢性肌腱疼痛的治疗效果。
