Abstract
Osteoarthritis (OA) is a highly prevalent joint disease that causes substantial disability, yet effective approaches to disease prevention or to the delay of OA progression are lacking. Emerging evidence has pinpointed ion channels as pivotal mediators in OA pathogenesis and as promising targets for disease-modifying treatments. Preclinical studies have assessed the potential of a variety of ion channel modulators to modify disease pathways involved in cartilage degeneration, synovial inflammation, bone hyperplasia and pain, and to provide symptomatic relief in models of OA. Some of these modulators are currently being evaluated in clinical trials. This review explores the structures and functions of ion channels, including transient receptor potential channels, Piezo channels, voltage-gated sodium channels, voltage-dependent calcium channels, potassium channels, acid-sensing ion channels, chloride channels and the ATP-dependent P2XR channels in the osteoarthritic joint. The discussion spans channel-targeting drug discovery and potential clinical applications, emphasizing opportunities for further research, and underscoring the growing clinical impact of ion channel biology in OA.
Key points
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Ion channels have key functions in the joints and emerge as important contributors to pathogenic processes in osteoarthritis (OA).
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Dysregulation of mechanical and biochemical stimuli activates ion channels such as TRPV4 and Piezo channels, leading to Ca2+ and Na+ influx, which contributes to cartilage destruction, inflammation and pain in OA.
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Some ion channels typically associated with peripheral neurons are also expressed in chondrocytes and immune cells, and have a crucial role in the pathophysiology of OA.
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Exploration of ion channel expression, interactions, and properties in joints, along with development of specific channel agonists and antagonists, has helped to accelerate research on their potential roles in OA.
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Several ion channel modulators have been recently tested in animal models and patients with OA, with encouraging results.
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Targeting of ion channels holds promise for the development of new and more effective OA treatment strategies.
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Acknowledgements
We are grateful to our gifted collaborators who made the explorations in our laboratories possible. Studies in our laboratories were supported by US National Institutes of Health research grants R01AR062207, R01AR061484, R01AR076900, R01AR078035 and R01NS103931. S.G.W. was supported by the Bridget Flaherty Endowment to the Yale Department of Neurology. We apologize to the colleagues whose papers were not cited owing to the constraints of word limitations.
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Glossary
- All-or-none action potentials
-
Neuronal signalling follows the all-or-none principle, whereby an action potential is generated and propagated along the axon without amplitude decrement when a neuron’s membrane potential reaches a stimulus-induced threshold, and no action potential occurs if the threshold is not reached.
- Designer receptors exclusively activated by designer drugs technology
-
(DREADD technology). A technology in neuroscience that remotely controls specific neurons by genetically engineering receptors unresponsive to endogenous ligands but activated by synthetic, designer drugs.
- Ferroptosis
-
Ferroptosis is an iron-dependent form of cell death characterized by lipid peroxidation and driven by iron accumulation and depletion of antioxidant enzymes.
- Glutathione peroxidase 4
-
(GPX4). An antioxidant enzyme that protects cells from ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols; inhibition or depletion of GPX4 results in lipid peroxide accumulation, thereby triggering ferroptosis.
- Purinergic receptors
-
Responsive to purine nucleotides and nucleosides such as ATP and adenosine, these receptors are classified into P1, P2Y and P2X types, with P1 and P2Y functioning as G protein-coupled receptors activated by adenosine and nucleotides such as ATP and adenosine diphosphate, respectively.
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Zhou, R., Fu, W., Vasylyev, D. et al. Ion channels in osteoarthritis: emerging roles and potential targets. Nat Rev Rheumatol 20, 545–564 (2024). https://doi.org/10.1038/s41584-024-01146-0
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DOI: https://doi.org/10.1038/s41584-024-01146-0
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