ORIGINAL RESEARCH article
Front. Mol. Neurosci.
Sec. Pain Mechanisms and Modulators
Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1583908
Bidirectional substance P signaling between periodontal ligament fibroblasts and sensory neurons under mechanical stress
Provisionally accepted- 1Department of Orthodontics, University Hospital Jena, Jena, Germany
- 2Section of Geriodontics, Department of Conservative Dentistry and Periodontics, University Hospital Jena, Jena, Germany
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Introduction: Orthodontic tooth movement (OTM) and treatment-associated pain are closely related processes driven by a local inflammatory response modulated by periodontal ligament fibroblasts (PdLFs). Increased levels of substance P (SP), a well-characterized tachykinin, has been demonstrated in the PdL following the application of orthodontic forces. Although traditionally considered as neurotransmitter modulating inflammatory processes and pain, recent evidence suggests that also non-neuronal cells contribute to SP signaling during OTM. Since sensory neurons also express the corresponding receptor NK1R, activation by SP appears to be possible. However, the contribution of PdLFs to SP signaling upon mechanical stress and their subsequent interaction with sensory neurons remain largely unexplored. Thus, the aim of the study was to investigate a potential SP-mediated interactions between PdLFs and sensory neurons advancing our understanding of molecular mechanisms underlying orthodontic pain during OTM.Methods: TAC1 and SP levels were quantified via qRT-PCR, Western blot, and ELISA in compressed human PdLFs. Their conditioned medium was applied to sensory-like SH-SY5Y neurons and their activation was assessed by morphological features, cFOS expression, and calcium influx. Conversely, PdLFs were stimulated with conditioned medium from capsaicin-activated SH-SY5Y neurons. Subsequently, cytokine expression, the RANKL/OPG ratio and the activation of immune cells and osteoclasts by PdLFs were evaluated.Compressive force induced a time-and intensity-dependent increase in TAC1 expression and SP secretion by compressed PdLFs with a peak at 24 hours. Stressed PdLFs significantly increased neurite complexity, cFOS levels and calcium influx in sensory neurons, indicating their activation. Conversely, activated neurons elicited a robust pro-inflammatory response in PdLFs along with an increased osteoclastogenesis.Discussion: Our findings demonstrate that PdL fibroblasts could function as a novel non-neuronal source of SP modulating sensory neuron activation. Conversely, fibroblasts were also stimulated by SP effecting inflammation and osteoclastogenesis. These findings underscore a dynamic role of PdLFand sensory neuron-derived SP that likely contributes to both pain perception and inflammatory bone remodeling during OTM.
Keywords: Nociception, Orthodontics, Periodontal ligament fibroblasts, Substance P, tac1
Received: 26 Feb 2025; Accepted: 29 Apr 2025.
Copyright: © 2025 Symmank, Löffler, Schulze-Späte and Jacobs. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Judit Symmank, Department of Orthodontics, University Hospital Jena, Jena, Germany
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