Na v 1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.

Autor: Fu W; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA.; Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA., Vasylyev D; Department of Neurology, Yale School of Medicine, New Haven, CT, USA.; Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare, West Haven, CT, USA., Bi Y; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., Zhang M; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., Sun G; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., Khleborodova A; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., Huang G; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA.; Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA., Zhao L; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA.; Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA., Zhou R; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA.; Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA., Li Y; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA.; Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA., Liu S; Department of Neurology, Yale School of Medicine, New Haven, CT, USA.; Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare, West Haven, CT, USA., Cai X; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., He W; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., Cui M; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., Zhao X; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA.; Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA., Hettinghouse A; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., Good J; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., Kim E; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., Strauss E; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., Leucht P; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., Schwarzkopf R; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA., Guo EX; Department of Biomedical Engineering, Columbia University, New York, NY, USA., Samuels J; Division of Rheumatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA., Hu W; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Attur M; Division of Rheumatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA., Waxman SG; Department of Neurology, Yale School of Medicine, New Haven, CT, USA. stephen.waxman@yale.edu.; Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare, West Haven, CT, USA. stephen.waxman@yale.edu., Liu CJ; Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA. chuan-ju.liu@yale.edu.; Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA. chuan-ju.liu@yale.edu.; Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA. chuan-ju.liu@yale.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Jan; Vol. 625 (7995), pp. 557-565. Date of Electronic Publication: 2024 Jan 03.
DOI: 10.1038/s41586-023-06888-7
Abstrakt: Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain 1 . Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes 2 , their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Na v 1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Na v 1.7 channels, with a density of 0.1 to 0.15 channels per µm 2 and 350 to 525 channels per cell. Serial genetic ablation of Na v 1.7 in multiple mouse models demonstrates that Na v 1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Na v 1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Na v 1.7 with selective or clinically used pan-Na v channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Na v 1.7 blockers regulate intracellular Ca 2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Na v 1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.
(© 2024. The Author(s).)
Databáze: MEDLINE
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