{"doi":"10.1002/ctm2.1634","title":"How do small quantities of cartilage sodium channels play a significant role in osteoarthritis?","abstract":"Osteoarthritis (OA) is a chronic degenerative joint disease affecting the entire joint, causing pain, stiffness and limitations in mobility and posing a significant burden on global health and the quality of life for millions worldwide.1 Despite its prevalence, treatment options remain limited, often focused on symptom management rather than addressing the underlying mechanisms driving joint degradation.2, 3 OA is characterized by the loss of cartilage, prompting most efforts to develop disease-modifying treatments to concentrate on molecular events within the cartilage. Our research has centred around the regulation of cartilage homeostasis and OA, with a specific focus on cartilage-degrading matrix-associated a disintegrin and metalloproteinase with thrombospondin type I motifs2 and inflammatory mediators, particularly tumour necrosis factor receptor signalling.4-8 In a recent report, our research revealed the presence and functionality of the sodium channel Nav1.7 (encoded by SCN9A) in cartilage cells, namely chondrocytes, highlighting Nav 1.7 as a novel therapeutic target for OA.9 Sodium channels are commonly highly expressed on excitable cells, such as neurons, muscle cells and cardiac myocytes.10 In an unbiased genetic screen for identifying the OA-associated molecules, Nav1.7 was, unexpectedly, found to be present and elevated in human OA chondrocytes.9 This intriguing and unexpected discovery that chondrocytes express functional Nav1.7 was validated through multiple assays, particularly a spectrum of electrophysiological and pharmacological methods. Subsequent serial genetic ablation of Nav1.7 in multiple mouse models demonstrated that dorsal root ganglion neuron-expressed Nav1.7 is involved in pain perception, whereas chondrocyte-expressed Nav1.7 governs OA progression as judged by both behaviour and anatomical methods. Additionally, pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav blockers can simultaneously attenuate the progression of OA and alleviate OA pain.9 Mechanistically, Nav1.7 deletion or blockade regulates chondrocytes biology and OA through enhancing HSP70 and midkine secretion.9 These findings demonstrate that in addition to controlling pain signalling in sensory neurons, Nav1.7 within chondrocytes plays a pivotal role in the progression of joint damage in OA. These findings not only better our understanding of the ion channel physiology as well as chondrocyte biology but also provide a basis for the development of Nav1.7 blockers as disease-modifying drugs for treating OA pathologically and symptomatically, thereby expanding appreciation of their clinical utility beyond that of pain killers. Nav1.7 opens a rich landscape of exploration and further investigation into the intricate mechanism governing chondrocyte function and cartilage homeostasis, providing fertile ground for translational research and drug development efforts. While recording sodium channel currents in chondrocytes poses significant challenges compared to neurons, our successful observations reveal the existence of functional Nav1.7 channels in human OA chondrocytes. These channels exhibit densities of 0.1–0.15 channels/μm2, with channel numbers ranging from 350 to 525 per cell—several orders of magnitude lower than in neurons.9 Patch-clamp recordings indicate that Nav1.7 is expressed in approximately 17% of OA chondrocytes.9 The key questions arising are why and how such a small number of Nav1.7 channels in chondrocytes play a substantial role in OA progression. Unravelling the intricate molecular mechanisms underlying this phenomenon warrants further investigation. In chondrocytes expressing Nav1.7, the blockade of Nav1.7 triggers increased secretion of HSP70 and midkine, which is crucial for Nav1.7 blockade-mediated regulation of chondrocyte biology, in turn impacting joint structure and pain in OA.9 The increased release of HSP70 and midkine upon Nav1.7 blockade of Nav1.7 expressing chondrocytes is possib","journal":"Clinical and Translational Medicine","year":2024,"id":444388,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":310622,"name":"Liu C","orcid":"0000-0002-7181-8032","position":1,"is_corresponding":false},{"id":1259488,"name":"Xiaohong Kong","orcid":"0009-0005-6982-9866","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-19T02:01:33.526738Z","pmid":"38530147","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}