Fibroblasts: the neglected cell type in peripheral sensitisation and chronic pain? A review based on a systematic search of the literature

Shinotsuka, Naomi; Denk, Franziska

doi:10.1136/bmjos-2021-100235

Cited by 10 publications

(8 citation statements)

References 61 publications

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“…In those patients without doppler positive synovial changes, persistent synovial cellular activity, for example, by fibroblasts, might mediate pain signalling, despite reduced synovial inflammation. This idea is discussed in more length in a recent publication from our centre 41 and is now under investigation.…”

Section: Discussionmentioning

confidence: 96%

Pain sensitisation and joint inflammation in patients with active rheumatoid arthritis

Chaabo,

Chan,

Garrood

et al. 2024

RMD Open

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IntroductionDespite better therapies and strategies, many people with rheumatoid arthritis (RA) have persistent pain, often from abnormal pain processing, now termed nociplastic pain. However, RA patients with fibromyalgia (FM), a central nociplastic pain syndrome, also have power doppler ultrasound (PDUS+) joint inflammation. To understand the complex causes of pain, we performed clinical examination and patient-reported outcome measures (PROMs) plus comprehensive PDUS evaluation not previously combined.MethodsIn a cross-sectional study of sequential RA patients with at least moderate DAS28 erythrocyte sedimentation rate disease activity, we assessed 66/68 joints for swelling and tenderness, respectively, FM American College of Rheumatology 2010 diagnostic criteria, completed PROMs for function, quality of life and mood, alongside PDUS examination of 44 joints. Statistical analysis included logistic regression modelling and regularised (lasso) logistic regression methods.ResultsFrom 158 patients, 72 (46%) patients met FM criteria, with significantly worse tender joint counts and PROMs, but no differences in PDUS compared with the non-FM group. Categorising patients by PDUS+ joint presence and/or FM criteria, we identified four distinct groups: 43 (27.2%) patients with −FM−PD, 43 (27.2%) with −FM+PD, 42 (26.6%) with +FM−PD and 30 (19%) with +FM+PD. Both FM+ groups had worse PROMs for fatigue, mood and pain, compared with the FM− groups. We were unable to develop algorithms to identify different groups.ConclusionThe unexpected group −FM−PD group may have peripheral nociplastic pain, not commonly recognised in rheumatology. Only 46% of patients demonstrated PDUS+ inflammation. However clinical examination and PROMs did not reliably differentiate groups, emphasising PDUS remains an important tool.

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Section: Discussionmentioning

confidence: 96%

Pain sensitisation and joint inflammation in patients with active rheumatoid arthritis

Chaabo,

Chan,

Garrood

et al. 2024

RMD Open

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“…Recently, crosstalk between neuronal and non-neuronal cells has received increasing attention (Song and Dityatev, 2018;Shinotsuka and Denk, 2022). Gaining precise knowledge about which cells express which molecules is important for future targeted approaches trying to intervene in specific pathways.…”

Section: Discussionmentioning

confidence: 99%

Analysis of matrisome expression patterns in murine and human dorsal root ganglia

Vroman,

Hunter,

Wood

et al. 2023

Front. Mol. Neurosci.

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The extracellular matrix (ECM) is a dynamic structure of molecules that can be divided into six different categories and are collectively called the matrisome. The ECM plays pivotal roles in physiological processes in many tissues, including the nervous system. Intriguingly, alterations in ECM molecules/pathways are associated with painful human conditions and murine pain models. Nevertheless, mechanistic insight into the interplay of normal or defective ECM and pain is largely lacking. The goal of this study was to integrate bulk, single-cell, and spatial RNA sequencing (RNAseq) datasets to investigate the expression and cellular origin of matrisome genes in male and female murine and human dorsal root ganglia (DRG). Bulk RNAseq showed that about 65% of all matrisome genes were expressed in both murine and human DRG, with proportionally more core matrisome genes (glycoproteins, collagens, and proteoglycans) expressed compared to matrisome-associated genes (ECM-affiliated genes, ECM regulators, and secreted factors). Single cell RNAseq on male murine DRG revealed the cellular origin of matrisome expression. Core matrisome genes, especially collagens, were expressed by fibroblasts whereas matrisome-associated genes were primarily expressed by neurons. Cell–cell communication network analysis with CellChat software predicted an important role for collagen signaling pathways in connecting vascular cell types and nociceptors in murine tissue, which we confirmed by analysis of spatial transcriptomic data from human DRG. RNAscope in situ hybridization and immunohistochemistry demonstrated expression of collagens in fibroblasts surrounding nociceptors in male and female human DRG. Finally, comparing human neuropathic pain samples with non-pain samples also showed differential expression of matrisome genes produced by both fibroblasts and by nociceptors. This study supports the idea that the DRG matrisome may contribute to neuronal signaling in both mouse and human, and that dysregulation of matrisome genes is associated with neuropathic pain.

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“…Other conditions associated with debilitating pain in which fibroblasts contribute include chronic pain, in which fibroblasts are responsible for releasing proalgesic mediators and sustaining inflammatory responses ( 86 ), or carpal tunnel syndrome, a peripheral neuropathy characterised by fibrosis occurring in the subsynovial connective tissue in the carpal tunnel, with fibroblast hyperplasia, disorganised collagen deposition and increased expression of TGF-β1 pathway components ( 87 ). Therapies using typical antifibrotic strategies like targeting this profibrotic pathway have shown promising preliminary results in this syndrome ( 88 , 89 ).…”

Section: Fibroblasts In Health and Diseasementioning

confidence: 99%

Melanocortin therapies to resolve fibroblast-mediated diseases

et al. 2023

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Stromal cells have emerged as central drivers in multiple and diverse diseases, and consequently, as potential new cellular targets for the development of novel therapeutic strategies. In this review we revise the main roles of fibroblasts, not only as structural cells but also as players and regulators of immune responses. Important aspects like fibroblast heterogeneity, functional specialization and cellular plasticity are also discussed as well as the implications that these aspects may have in disease and in the design of novel therapeutics. An extensive revision of the actions of fibroblasts on different conditions uncovers the existence of numerous diseases in which this cell type plays a pathogenic role, either due to an exacerbation of their 'structural' side, or a dysregulation of their 'immune side'. In both cases, opportunities for the development of innovative therapeutic approaches exist. In this regard, here we revise the existing evidence pointing at the melanocortin pathway as a potential new strategy for the treatment and management of diseases mediated by aberrantly activated fibroblasts, including scleroderma or rheumatoid arthritis. This evidence derives from studies involving models of in vitro primary fibroblasts, in vivo models of disease as well as ongoing human clinical trials. Melanocortin drugs, which are pro-resolving mediators, have shown ability to reduce collagen deposition, activation of myofibroblasts, reduction of pro-inflammatory mediators and reduced scar formation. Here we also discuss existing challenges, both in approaching fibroblasts as therapeutic targets, and in the development of novel melanocortin drug candidates, that may help advance the field and deliver new medicines for the management of diseases with high medical needs.

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Fibroblasts: the neglected cell type in peripheral sensitisation and chronic pain? A review based on a systematic search of the literature

Cited by 10 publications

References 61 publications

Pain sensitisation and joint inflammation in patients with active rheumatoid arthritis

Pain sensitisation and joint inflammation in patients with active rheumatoid arthritis

Analysis of matrisome expression patterns in murine and human dorsal root ganglia

Melanocortin therapies to resolve fibroblast-mediated diseases

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