ABSTRACT
Objective
Sympathetic‐sensory coupling is increasingly implicated in joint homeostasis and disease. Towards the long‐term goal of deciphering its role in temporomandibular disorders (TMDs), we characterised the spatial relationships of sympathetic and sensory nerves and their receptors in the mouse temporomandibular joint (TMJ) and trigeminal ganglion (TG), using the knee joint for comparison.
Materials and Methods
RNAscope was used for localisation of sympathetic nerve markers tyrosine hydroxylase (Th) and adrenergic receptor alpha 2a (Adrα2a); and brain‐derived neurotrophic factor (Bdnf) and its receptor neurotrophic receptor tyrosine kinase 2 (Ntrk2) that stimulate sympathetic nerve growth. Sensory marker calcitonin gene‐related peptide (CGRP) was detected through immunofluorescence.
Results
Th, Adrα2a, Bdnf and Ntrk2 were expressed in the TMJ and knee joint tissues, including condylar and disc cartilages, muscles and bone marrow. CGRP+ sensory neurons were abundant in the TG and, to a lesser extent, in TMJ and knee tissues, where they were often located near Th‐ or Adrα2a‐expressing sympathetic cells. Some CGRP+ neurons in the TG also co‐expressed Adrα2a.
Conclusion
Our findings reveal the presence of sympathetic and sensory nerves within the TMJ, knee joint and TG, with these nerves often located near each other. Along with the presence of Adrα2a on CGRP+ sensory fibres, this suggests sympathetic‐sensory coupling and potential crosstalk in physiologic and pathologic responses. Expression of Bdnf and Ntrk2 in the TMJ and knee implicates this neurotrophin signalling in modulating sympathetic activity via neural sprouting. Further studies will clarify the functional contributions of this neurological architecture to tissue homeostasis, disease and pain.
Keywords: knee joint, sensory nerve, sympathetic nerve, TMJ, trigeminal ganglion
1. Introduction
Temporomandibular disorders (TMDs) encompass a highly prevalent constellation of musculoskeletal disorders that affect the temporomandibular joint (TMJ) and associated orofacial tissues, often leading to chronic pain, functional impairment and a diminished quality of life [1]. The unknown and likely multifactorial aetiology of TMDs presents challenges in both diagnosis and treatment. Mechanical stress, inflammation and altered neural activity are recognised as primary contributors to TMD‐associated pain. Chronic stress, whether as a primary trigger or a response to ongoing TMD‐related pain, is known to exacerbate symptoms, likely through heightened sympathetic nervous system (SNS) activity [2]. Thus, understanding the neurobiological mechanisms underlying TMD‐related nociception is essential to developing effective therapeutic strategies.
SNS activity plays a crucial role in modulating pain, inflammatory responses and tissue homeostasis in diarthrodial joints [3, 4, 5]. In the TMJ, sympathetic regulation involves multiple signalling pathways, including catecholamine (epinephrine and norepinephrine [NE]) activation of adrenergic receptors (Adrs). Interestingly, Adrs and other neural receptors are not only found on nerves but also in several non‐neuronal cells, including those in musculoskeletal tissues, where they help maintain homeostasis and their dysregulation contributes to disease. Among these Adrs, α2A‐ADR (encoded by Adrα2a) mediates catecholamine‐driven effects on neuronal excitability and inflammatory responses and is involved in arthralgia and joint pathology in experimental models [6].
The TMJ receives sensory innervation primarily from branches of the mandibular nerve (V3), including the auriculotemporal, masseteric and deep temporal nerves, which transmit sensory information to the trigeminal ganglion (TG) [7]. Sensory nerves, predominantly from the TG, transmit pain signals via neuropeptides such as calcitonin gene‐related peptide (CGRP), which amplify nociceptive responses, particularly under pathological conditions [8]. Sympathetic nerves, on the other hand, release catecholamines, which sensitise sensory neurons and exacerbate pain through a mechanism known as sympathetic‐sensory coupling [9]. This bidirectional interaction is increasingly recognised as a critical mechanism in joint pain, yet its precise role in TMJ pain modulation remains unclear [10, 11].
In addition to sympathetic‐sensory interactions, neurotrophic factors, including brain‐derived neurotrophic factor (BDNF) and its receptor neurotrophic receptor tyrosine kinase 2 (NTRK2, also named TrkB), play critical roles in neuronal survival, growth and synaptic plasticity [12]. BDNF signalling is known to influence sensory neuron excitability and nociceptive sensitivity in inflammatory conditions, and it has been implicated in sympathetic nerve sprouting, which may further contribute to pain modulation [13, 14, 15]. Collectively, these molecular mediators and pathways of the peripheral sensory and SNSs combined with neurotrophic mechanisms create a complex neural microenvironment capable of shaping joint homeostasis and modulating pain and other pathologic changes.
Despite growing recognition of sympathetic‐sensory interactions and neurotrophic modulation in joint pain, the spatial organisation and expression patterns of these systems within the TMJ and TG remain unclear. To address this gap, we investigated the spatial localisation of sensory (CGRP), sympathetic (tyrosine hydroxylase Th), Adrs and neurotrophic (Bdnf, Ntrk2) markers in the TMJ and TG of mice. To determine whether sensory‐sympathetic interactions in the TMJ follow a broader neural organisational pattern, we examined the knee joint as a comparative model. Our findings revealed the presence of sensory and sympathetic fibres within the TMJ, knee joint and TG frequently in close spatial association with each other. Additionally, Bdnf and Ntrk2 exhibited expression patterns that are similar to sympathetic markers. The findings provide foundational insights that are critical for advancing targeted therapeutic strategies to alleviate chronic joint pain and restore functional integrity.
2. Materials and Methods
2.1. Tissue Preparation and Staining
The TMJs and knee joints were from previous studies on 12‐week‐old female C57BL/6J control mice (Charles River Laboratories) following approval from the Institutional Animal Care and Use Committee at University of Michigan. The TG samples were obtained post euthanasia from control mice following approval from the Institutional Animal Care and Use Committee at University of California, Los Angeles. The entire TMJ, knee joints or TG were retrieved from euthanised mice and fixed overnight at 4°C with 4% paraformaldehyde (PFA) in PBS. The joints were decalcified in 0.5 M EDTA for 2 weeks, processed through serial ethanol washes, embedded in paraffin and 7 μm thick sections prepared. For frozen sections, TG was processed through serial sucrose washes and embedded in Tissue‐Tek O.C.T. Compound (Sakura). and 10 μm sections prepared.
RNAscope Multiplex Fluorescent v2 Assay (Advanced Cell Diagnostics) combined with immunostaining was carried out following the manufacturer's instructions. Frozen tissue sections were washed in 1× PBS to remove residual OCT, slides baked at 60°C for 30 min and post‐fixed in 4% PFA in PBS at 4°C for 15 min. For paraffin‐embedded sections, slides were baked in a dry air oven at 60°C for 30 min, followed by deparaffinisation, rehydration, and air dried for 5 min at room temperature. Antigen retrieval was performed by immersing slides in pre‐heated Co‐Detection Target Retrieval buffer (98°C) for 5 min. Tissues were treated with hydrogen peroxide for 10 min at room temperature and incubated overnight at 4°C with primary antibody (Rabbit anti‐mouse GGRP from Invitrogen) at 1:100 dilution in Co‐Detection Antibody Diluent. Post‐primary fixation was performed in 10% neutral buffered formalin for 30 min. Protease treatment was carried out using RNAscope Protease III for 15 min (TG sections) or 20 min (joint sections) at 40°C. RNAscope Multiplex Fluorescent v2 assay was performed according to manufacturer instructions. Finally, secondary antibody incubation was performed to complete the immunofluorescence detection. Opal 520, 570 and 690 from Akoya Biosciences were used for colour development. A RNAscope 3‐plex Negative Control Probe (Advanced Cell Diagnostics) consistently showed no background staining (Figure S1). RNAscope Mus musculus probes for Adrα2a, Th, Bdnf and Ntrk2 were purchased from Advanced Cell Diagnostics. Sections were imaged using Leica 880 confocal microscopy. Images were analysed by ImageJ.
2.2. Statistics and Reproducibility
All experiments were replicated at least three times, and no data were excluded. Representative images are shown in figures.
3. Results
3.1. Spatial Distribution of Sympathetic and Neurotrophic Signalling Genes in the TMJ and Knee Joint
RNAscope in situ hybridisation demonstrated the presence of sympathetic nerve‐associated genes Adrα2a and Th, along with the neurotrophic factors Ntrk2 and Bdnf, in multiple tissue compartments, including bone marrow, fibrocartilaginous structures, muscle fibres and cartilage of both the TMJ and knee joint (Figure 1). Confocal imaging revealed abundant punctate signals in the bone marrow of both the TMJ and knee joint, indicating strong expression of sympathetic and neurotrophic factors in vascularised regions. A similar pattern was observed in the articular eminence of the TMJ and the metaphyseal bone of the knee joint, suggesting a conserved neurovascular distribution across these structurally distinct sites. In addition to osseous structures, Adrα2a and Th signals were detected along muscle fibres in both joints, with Adrα2a expression being more pronounced in knee joint muscle fibres than in the TMJ. Similarly, fibrocartilaginous structures, including the articular disc in the TMJ, displayed widespread expression of sympathetic and neurotrophic markers. Overall, Ntrk2 and Bdnf exhibited higher expression levels than Th and Adrα2a in both the TMJ and knee joint.
FIGURE 1.
Sympathetic and neurotrophic signalling genes in the TMJ and Knee Joint. RNAscope illustrates the localisation of sympathetic nerve genes (Adrα2a, Th) and neurotrophic signalling genes (Ntrk2, Bdnf) in various tissues of the TMJ (A, B) and knee joint (C, D). Scale bars: 10 μm in A1–4, B1–4, C1–4, D1–4; 260 μm in A–D.
Joint‐specific differences were observed in the cartilage regions of the two joints (Figure 2), despite the overall similar expression patterns of these mRNAs in surrounding tissues such as muscle and bone marrow. While Adrα2a, Th, Bdnf, and Ntrk2 were detected in both joints, their spatial distributions varied between anatomical sites. In the TMJ, the highest expression of these markers was in the middle region of the condylar cartilage. In contrast, the knee joint displayed differential gene expression between the femoral and tibial cartilage, with higher expression in the mid‐posterior region of femoral cartilage and the mid‐anterior region of tibial cartilage. Notably, in both joints, expression was enriched in hypertrophic chondrocytes adjacent to the subchondral bone.
FIGURE 2.
Localisation of sympathetic and neurotrophic signalling genes in the cartilage of TMJ and Knee joint. RNAscope of (A, B) Bdnf and its receptor Ntrk2; (C, D) Adrα2a and Th, a sympathetic nerve marker in TMJ and knee cartilage. Enlargements of the areas are outlined in yellow in A2, B1, C2, D1. Anterior (Ant), Middle (Mid), Posterior (Post). Scale bars: 10 μm in A1–2, C1–3; 130 μm in B1, D1; 260 μm in A–D; 1 μm in yellow boxes in A2, C2; 13 μm in yellow boxes in B1, D1.
3.2. Spatial Proximity of Sensory Nerves and Sympathetic Nerves in TG, TMJ and Knee Joint
To explore the spatial relationships between sensory and sympathetic nerves in the TG, TMJ and knee joint, we performed co‐detection of CGRP alongside Th and Adrα2a. In the TG, CGRP+ neurons and fibres formed an extensive network throughout the ganglion, with Th+ cells frequently positioned in close association with CGRP+ neurons (Figure 3). Interestingly, a subset of CGRP+ neurons co‐expressed Adrα2a, suggesting that certain sensory neurons within the TG may receive direct adrenergic modulation from sympathetic activation.
FIGURE 3.
Sensory nerves found in close proximity to sympathetic nerves in TG, TMJ and knee joint. RNAscope with immunostaining reveals the close association of sensory and sympathetic neurons and fibres in the TG (A, A1, A2, B, B1, B2), TMJ (C, D), and knee joint (E, F). Scale bars: 10 μm in A to F; 5 μm in A1, A2, B1; 2 μm in B2.
To determine whether these sensory‐sympathetic associations extended peripherally to joint tissues, we next examined these markers in the TMJ and knee joint. Although CGRP+ fibres were less abundant in both joints than in the TG, they were consistently found adjacent to Th+ or Adrα2a+ cells—particularly within vascularised and fibrocartilaginous regions, such as the bone marrow and articular disc (Figure 3). In contrast, cartilage in both joints lacked CGRP+ labelling, indicating limited direct sensory innervation in these areas.
Figure 4 illustrates the expression patterns of each of the markers we studied across joint compartments. In both the TMJ and knee joint, sensory and sympathetic markers were predominantly detected in vascularised and fibrocartilaginous structures, including the bone marrow, muscle and articular disc or metaphyseal bone, respectively. These findings indicate that sensory‐sympathetic interactions extend beyond the TG to peripheral joints, suggesting a conserved pattern of sensory‐sympathetic organisation across distinct joint types. Similarly, Ntrk2 and Bdnf exhibited spatial expression patterns comparable to those of sympathetic markers in both joints.
FIGURE 4.
Sensory, sympathetic and neurotrophic signalling genes in the TMJ and knee joint. This schematic illustrates the spatial localisation of sensory nerve protein (CGRP), sympathetic genes (Adrα2a, Th) and neurotrophic signalling genes (Ntrk2, Bdnf) in the TMJ (top panels) and the knee joint (bottom panels). Gene and protein expression are mapped across various anatomical structures, including the articular disc, bone marrow, cartilage, epiphyseal growth plate, meniscus, metaphyseal bone, muscle and subchondral bone.
4. Discussion
Our study advances an understanding of the neural complexity within the TG, TMJ and knee joint by demonstrating that sensory, sympathetic and neurotrophic circuits are intricately co‐localised within these tissues. By examining the expression patterns of key sympathetic‐associated genes (Th, Adrα2a), neurotrophic factors (Bdnf, Ntrk2) and the sensory marker CGRP, we reveal that these molecular networks converge within fibrocartilaginous, vascularised and innervated regions of joint musculoskeletal tissues and TG. This integrated network is likely to influence joint homeostasis, tissue remodelling and pain modulation. These findings, together with prior studies showing that sympathetic neurotransmitters amplify nociceptive signalling in sensory neurons [16, 17], suggest a mechanism for sympathetic‐sensory coupling in potentiating or perpetuating chronic pain in musculoskeletal disorders [17, 18, 19].
Our findings demonstrate that sympathetic‐associated genes (Th and Adrα2a) and sensory markers (CGRP) are in proximity in several key compartments both in the TMJ and the knee joint, including bone marrow, muscle fibres and fibrocartilaginous tissues. In the TG, the frequent juxtaposition of Th + cells with CGRP+ neurons, as well as the co‐expression of Adrα2a in a subset of CGRP+ neurons, suggests potential sites of direct sympathetic‐sensory interaction. SNS neurotransmitters, including NE, epinephrine and dopamine, act on a wide range of targets, from neurons to non‐neuronal tissues. Their effects depend on the type and distribution of adrenergic receptors (α1, α2, β1, β2 and β3) in each tissue [20]. Among these, α2A‐ADR (encoded by Adrα2a) and β2‐ADR (encoded by Adrb2) are particularly enriched in musculoskeletal tissues, sensory nerves and immune cells [21]. Consistent with this, we identified Adrα2a expression in TMJ musculoskeletal tissues. SNS activation by chronic stress or mechanical dysfunction increases local NE levels. Such activation has been shown to reduce bone quality and diminish cartilage integrity [6]. Indeed, mechanical dysfunction alone, even in the absence of chronic stress, can impair subchondral bone acting via α2‐ and β2‐ADR signalling [22].
Sympathetic–sensory interaction is also known to regulate various physiological processes, such as kidney development and homeostasis [23]. In the orofacial region, sympathetic activation has been shown to heighten sensory nerve excitability, intensifying nociceptive signalling, which is particularly relevant in TMDs. Similarly, psychological stress‐induced sympathetic activation exacerbates nociceptive responses, thereby sustaining chronic pain [24, 25]. In TMJ osteoarthritis, increased sympathetic innervation of the subchondral bone is observed to precede sensory nerve growth, contributing to pain progression. The knee joint similarly exhibits sensory and sympathetic fibre sprouting in the synovial membrane and periosteum in painful arthritis in aged mice [10]. This aligns with our data showing the low abundance of CGRP+ fibres in healthy joints. Moreover, sympathetic neural inputs, particularly through NE release, are known to promote sensory nerve growth and excitability, further amplifying pain signalling [22, 26, 27]. Blocking sympathetic activity in these models has been shown to alleviate pain, highlighting the therapeutic potential of targeting maladaptive sensory–sympathetic interactions [28, 29].
Comparative observations between the TMJ and knee joint allow for the identification of shared or joint‐specific patterns of sympathetic‐sensory relationships and offer insights into whether sympathetic‐sensory coupling is a conserved mechanism across different joint environments. Although the overall patterns of nerve markers were conserved across the TMJ and knee joint, regional differences likely reflect joint‐specific functional demands. For instance, the knee joint exhibited stronger expression of Adrα2a and Th in muscle fibres compared to the TMJ. Additionally, differential expression patterns within cartilage regions suggest that mechanical loading and joint biomechanics influence sympathetic and neurotrophic signalling [30]. These variations may contribute to differing susceptibilities of joints to degenerative changes and pain phenotypes, emphasising the role of biomechanical forces in shaping the neural microenvironment [31, 32]. Because TMJ and knee joints differ substantially in their anatomy and biomechanics, this likely influences the baseline expression of neural markers. However, since our findings are qualitative in nature, they should be interpreted with caution.
Another notable aspect of our study is the prominent expression of the neurotrophic factors Bdnf and Ntrk2 across the examined tissues. Neurotrophic signalling is critical for neuronal survival, differentiation and plasticity [33], and has been implicated in chronic pain, where they enhance nociceptive sensitivity and central sensitisation [34, 35]. In our studies, both Bdnf and Ntrk2 were abundant in the TMJ and knee joint and spatially associated with sympathetic markers. This implies that neurotrophins might synergise with sympathetic inputs to regulate nerve growth, enhance sensory neuron excitability and potentially contribute to maladaptive plasticity under pathological conditions. Aligning with these findings, previous studies have shown that Bdnf directs sympathetic axon growth during development and facilitates sympathetic sprouting following nerve injury [36]. These mechanisms are particularly relevant to joint diseases such as osteoarthritis, where Bdnf sensitises afferent neurons in the knee during early inflammation and subsequently impacts bone afferents as the pathology advances [15].
Traditionally, cartilage has been considered as an aneural tissue. Although cartilage is generally devoid of direct innervation, transient penetration of nerve fibres into outer layers and cartilage canals has been documented during the formation of secondary ossification centers [37]. In neonatal rat joints, nerve fibres have been shown to interact with chondrocytes, potentially regulating cartilage development. In adult joints, nerve fibres have been identified in the periosteum, superficial cartilage layers and osteoarthritic cartilage. Our study detected the expression of Ntrk2, Bdnf, Adrα2a and Th in cartilage and adjacent regions, while CGRP‐positive sensory fibres were notably absent. This pattern implies that neurotrophic and sympathetic signals may indirectly influence cartilage homeostasis through paracrine signalling from the subchondral bone or fibrocartilaginous interfaces [38, 39]. Moreover, our preliminary findings (data not shown) further identify ADR and neurotrophic (Ntrk2) pathways as significantly elevated in female fibrocartilage compared to male. We also observed dimorphism in α1‐ and β2‐ADR expression in masticatory muscle afferent fibres, suggesting heightened responsiveness of female TMJ musculoskeletal cells to catecholamines and neurotrophins. This may contribute to sex‐specific vulnerabilities in TMD pathogenesis.
In summary, our study broadens the understanding of the neural complexity within joint tissues by demonstrating the co‐localisation of sympathetic and sensory‐associated genes, as well as the expression of neurotrophic markers. These findings underscore the likelihood of sensory‐sympathetic‐neurotrophic interactions in maintaining joint homeostasis and tissue integrity, as well as contributing to disease when dysregulated. The findings provide a framework for future research on the functional implications of these interrelated neural circuits and interactions in pathological conditions, such as TMDs, osteoarthritis and nociception. Elucidating these mechanisms will be instrumental in identifying therapeutic targets to alleviate pain, preserve joint function and improve quality of life for patients.
5. Conclusion
In conclusion, our study localises and highlights the spatial relationships between sensory, sympathetic and neurotrophic markers in the TG, TMJ and knee joint. In the TG, the close proximity of Th‐expressing cells and CGRP+ sensory neurons, along with Adrα2a expression in a subset of CGRP+ neurons, suggests a spatial association between adrenergic signalling and sensory nerve activity. In peripheral joints, the close spatial arrangement of cells expressing sympathetic associated genes (Th and Adrα2a) and CGRP+ sensory fibres further highlights the spatial connection between sympathetic and sensory signalling. We note that such spatial proximity does not directly demonstrate a functional interaction. Additionally, the neurotrophic ligand Bdnf and its receptor Ntrk2 are prominent in the TMJ and knee joint. Together, these findings offer valuable insight into the spatial organisation of sympathetic, sensory and neurotrophic signalling within joints, which could guide future research into their functional roles in health and disease.
Author Contributions
Conceptualization: S.K., Q.Y., A.M.; Methodology: Q.Y., A.M., S.K.; Validation: Q.Y., A.M., S.K., X.Z., K.K.U.; Data curation: Q.Y., A.M., X.Z., K.K.U., S.K.; Writing – original draft: Q.Y., A.M., S.K.; Writing – review and editing: S.K., Q.Y., A.M.; Visualisation: Q.Y.; Project administration: S.K.; Funding acquisition: S.K.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Figure S1: ocr70031‐sup‐0001‐FigureS1.docx.
Acknowledgements
We acknowledge the UCLA Broad Stem Cell Research Center Microscopy Core for providing confocal microscopy. This study was funded by the NIH/NIDCR 1R34DE033595‐01 to Dr. Sunil Kapila.
Funding: This study is funded by the NIH/NIDCR 1R34DE033595‐01 to Dr. Sunil Kapila and by R25DE030117‐02 and the QCBio Collaboratory Fellowship 2024/2025 to Dr. Karolina Elżbieta Kaczor‐Urbanowicz.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: ocr70031‐sup‐0001‐FigureS1.docx.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.