{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:55:11Z","timestamp":1790391311381,"version":"4.1.0"},"reference-count":91,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Eurospine, The Spine Society of Europe","award":["2023-027"],"award-info":[{"award-number":["2023-027"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Intervertebral disc degeneration is characterized by inflammation, extracellular matrix breakdown, and neurovascular ingrowth, processes that contribute to discogenic, chronic back pain. The transient receptor potential canonical 6 (TRPC6) channel is a calcium-permeable ion channel implicated in inflammation and pain signaling in multiple tissues; however, its functional role in human disc cells remain unknown. Here, we investigated the expression, activation, and downstream consequences of TRPC6 activation using Hyp9, a pharmacological activator of TRPC6. TRPC6 transcripts were consistently detected across all donors examined (n = 17). Functional TRPC6 activation induced a rapid, dose-dependent calcium (Ca2+) influx across 0.5\u2013100 \u00b5M Hyp9. TRPC6 activation did not reduce metabolic activity or increase cytotoxicity at concentrations commonly used for in vitro TRPC6 activation. Mechanistically, TRPC6 activation induced mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-\u03baB) pathways, as demonstrated by increased phosphorylation of p38 and extracellular signal-regulated kinase (ERK), degradation of the inhibitor of \u03baB-alpha (I\u03baB-\u03b1), and increased nuclear translocation of the NF-\u03baB p65 subunit. Downstream of these early signaling events, TRPC6 activation elicited a robust inflammatory and catabolic response with upregulation of IL-6, IL-8, COX-2, MMP-1, MMP-3, NGF, and VEGF, with corresponding increases in protein secretion. These findings identify TRPC6 as an important signaling node linking calcium influx to inflammatory, catabolic, and neuro- and angiogenesis-associated pathways in disc cells, highlighting TRPC6 as a potential therapeutic target in degenerative disc disease.<\/jats:p>","DOI":"10.3390\/cells15060534","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T12:42:16Z","timestamp":1773751336000},"page":"534","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["TRPC6-Mediated Ca2+ Influx Activates MAPK and NF\u03baB Signaling and Elicits Pro-Inflammatory and Catabolic Responses in Human Intervertebral Disc Cells"],"prefix":"10.3390","volume":"15","author":[{"given":"Janitri","family":"Venkatachala Babu","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Rochester Institute of Technology (RIT), Rochester, NY 14623, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varun","family":"Puvanesarajah","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Physical Performance, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Addisu","family":"Mesfin","sequence":"additional","affiliation":[{"name":"MedStar Orthopaedic Institute, MedStar Georgetown University Hospital, Washington, DC 20010, USA"},{"name":"Department of Orthopaedic Surgery, Georgetown University School of Medicine, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8723-7682","authenticated-orcid":false,"given":"Jonathan P.","family":"Japa","sequence":"additional","affiliation":[{"name":"MedStar Orthopaedic Institute, MedStar Georgetown University Hospital, Washington, DC 20010, USA"},{"name":"Department of Orthopaedic Surgery, Georgetown University School of Medicine, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Yoon","sequence":"additional","affiliation":[{"name":"MedStar Orthopaedic Institute, MedStar Georgetown University Hospital, Washington, DC 20010, USA"},{"name":"Department of Orthopaedic Surgery, Georgetown University School of Medicine, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Ehioghae","sequence":"additional","affiliation":[{"name":"MedStar Orthopaedic Institute, MedStar Georgetown University Hospital, Washington, DC 20010, USA"},{"name":"Department of Orthopaedic Surgery, Georgetown University School of Medicine, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Schrlau","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, Rochester Institute of Technology (RIT), Rochester, NY 14623, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7015-2101","authenticated-orcid":false,"given":"Laura S.","family":"Stone","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Faculty of Medicine, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7696-1479","authenticated-orcid":false,"given":"Wolfgang","family":"Hitzl","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Optometry, Paracelsus Medical University, 5020 Salzburg, Austria"},{"name":"Research Program, Experimental Ophthalmology and Glaucoma Research, Paracelsus Medical University, 5020 Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3281-4629","authenticated-orcid":false,"given":"Karin","family":"Wuertz-Kozak","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Rochester Institute of Technology (RIT), Rochester, NY 14623, USA"},{"name":"Sch\u00f6n Clinic Munich Harlaching, Spine Center, Academic Teaching Hospital and Spine Research Institute of the Paracelsus Medical University, 5020 Salzburg, Austria; 81547 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1016\/S0140-6736(18)32279-7","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017","volume":"392","author":"Spencer","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"299","DOI":"10.21037\/atm.2020.02.175","article-title":"Global low back pain prevalence and years lived with disability from 1990 to 2017: Estimates from the Global Burden of Disease Study 2017","volume":"8","author":"Wu","year":"2020","journal-title":"Ann. 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