Background & Aims

Osteoarthritis (OA) is a progressive joint condition marked by persistent joint pain [1]. Joints, abundantly supplied with sensory nerves, experience chronic pain due to heightened nociceptive signals from the affected OA joints. This process sensitizes both peripheral and central nervous systems, contributing to the manifestation of persistent pain. Transient Receptor Potential Melastatin 3 (TRPM3) is expressed in sensory neurons and plays a role in detecting noxious heat and contributing to inflammatory heat hyperalgesia [2]. Consequently, we investigated whether TRPM3 might also act as a mediator of OA pain.

Methods

We utilized genetically modified animals, pharmacological tools, and behavioural assessments to investigate the involvement of the TRPM3 ion channel in pain behaviours associated with OA induced by monosodium iodoacetate (MIA) and partial meniscectomy in mice. The dorsal root ganglion (DRG) level of TRPM3 mRNA was evaluated using quantitative polymerase chain reaction (qPCR) in both sham-operated and meniscectomized mice.

Results

The global deletion of Trpm3 prevented the establishment of pain behaviours in both OA models, despite not preventing the development of OA pathology. Importantly, the sensory neuron-specific deletion of Trpm3, by crossing Advillin-Cre and Trmp3fl/fl (containing loxP sites flanking Trpm3) mice, prevented the development of OA pain in meniscectomized mice, mimicking the effects of the global deletion of Trpm3. Meniscectomy did not induce alterations in the expression levels of Trpm3 transcript within the DRG. Crucially, animals without Trpm3 in sensory neurons (AdvCreTrpm3fl/fl) demonstrated a significant decrease in Trpm3 levels. Furthermore, the specific TRPM3 channel antagonist ononetin successfully reversed established OA pain in meniscectomized mice.

Conclusions

Our results demonstrate that TRPM3 expressed in sensory neurons mediates OA pain in mice and indicate that selective antagonists for the channel are potential therapeutic approaches to treat chronic pain associated with OA.

References

[1] Goldring SR, Goldring MB. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk. Nat Rev Rheumatol. 2016 Nov;12(11):632-644. doi: 10.1038/nrrheum.2016.148. Epub 2016 Sep 22. PMID: 27652499.

[2] Behrendt M. Transient receptor potential channels in the context of nociception and pain – recent insights into TRPM3 properties and function. Biol Chem. 2019 Jun 26;400(7):917-926. doi: 10.1515/hsz-2018-0455. PMID: 30844758.

Presenting Author

Robson da Costa

Poster Authors

Robson da Costa

PhD

Universidade Federal do Rio de Janeiro

Lead Author

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Clive Gentry

Wolfson SPaRC, King's College, London, UK

Lead Author

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Fabiana C. Dias

PhD

1. UFRJ, Rio de Janeiro, Brazil. 2. Wolfson SPaRC, King's College, London, UK

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Margot Maurer

IoPPN, King's college London

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Laura I. Primicheru

MSc

Wolfson SPaRC, King's College, London, UK

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Stefanie Mannebach

Experimental and Clinical Pharmacology and Toxicology. Saarland University, Homburg, Germany.

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Petra Weissgerber

PhD

Experimental and Clinical Pharmacology and Toxicology. Saarland University, Homburg, Germany.

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Marc Freichel

PhD

Pharmacological Institute, Ruprecht-Karls-University Heidelberg, Germany

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Stephan E. Philipp

PhD

Experimental and Clinical Pharmacology and Toxicology. Saarland University, Homburg, Germany.

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David Andersson

PhD

Wolfson SPaRC, King's College, London, UK

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Stuart Bevan

PhD

Wolfson SPaRC, King's College, London, UK

Lead Author

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Topics

  • Joint Pain