LncRNA HOXC-AS3 Prevents Chondrocyte Senescence and Osteoarthritis Progression Through miR-615-3p Sponging and RRBP1 Interaction

LncRNA HOXC-AS3 Prevents Chondrocyte Senescence and Osteoarthritis Progression Through miR-615-3p Sponging and RRBP1 Interaction | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article LncRNA HOXC-AS3 Prevents Chondrocyte Senescence and Osteoarthritis Progression Through miR-615-3p Sponging and RRBP1 Interaction Chan Wang, Jun zhou, Lulu Chen, Changyan Ma, Zhan Dong, Dengshun Miao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6379719/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Feb, 2026 Read the published version in Cell & Bioscience → Version 1 posted 4 You are reading this latest preprint version Abstract Background: Osteoarthritis (OA) is a prevalent chronic joint disease characterized by progressive cartilage degeneration, significantly impairing quality of life for millions worldwide. Cellular senescence has emerged as a pivotal driver of OA pathogenesis, with senescent chondrocytes exhibiting a senescence-associated secretory phenotype that exacerbates tissue degradation. Long non-coding RNAs (lncRNAs) play critical roles in cartilage homeostasis, yet their regulatory mechanisms in OA remain incompletely understood. This study aimed to investigate the expression patterns, biological functions, and underlying mechanisms of lncRNA HOXC-AS3 in chondrocyte biology and OA pathogenesis. Results: LncRNA HOXC-AS3 was significantly downregulated in both OA cartilage tissues and IL-1β-treated human chondrocytes. Functional experiments demonstrated that HOXC-AS3 knockdown inhibited chondrocyte proliferation, promoted cellular senescence, and caused extracellular matrix imbalance, while its overexpression effectively reversed IL-1β-induced chondrocyte dysfunction. Mechanistic investigations revealed that HOXC-AS3 functions through dual molecular mechanisms: serving as a competing endogenous RNA by directly binding to miR-615-3p, and interacting with ribosome-binding protein 1 (RRBP1). Both mechanisms converged to regulate the expression of citron rho-interacting serine/threonine kinase (CIT), a key cell cycle regulator. Notably, CIT knockdown recapitulated the cellular phenotypes observed with HOXC-AS3 deficiency, while HOXC-AS3 overexpression rescued chondrocyte function by maintaining CIT expression levels even under inflammatory conditions. Conclusions: Our study identifies lncRNA HOXC-AS3 as a critical regulator of chondrocyte homeostasis that protects against OA progression through novel dual mechanisms: miR-615-3p sponging and RRBP1 interaction, both converging to maintain CIT expression. These findings not only enhance our understanding of the complex regulatory networks underlying OA pathogenesis but also highlight HOXCAS3 and its downstream effectors as potential therapeutic targets for OA treatment. Osteoarthritis chondrocyte senescence long non-coding RNA HOXC-AS3 miR-615-3p RRBP1 CIT extracellular matrix cellular homeostasis RNA-protein interaction Full Text Supplementary Files OriginalimagesofWesternblot.pdf Cite Share Download PDF Status: Published Journal Publication published 15 Feb, 2026 Read the published version in Cell & Bioscience → Version 1 posted Reviewers agreed at journal 01 Aug, 2025 Reviewers invited by journal 16 Jun, 2025 Editor assigned by journal 07 Apr, 2025 First submitted to journal 05 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6379719","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":471910980,"identity":"4243280e-efb3-4d91-865c-8ae9b5c9b750","order_by":0,"name":"Chan Wang","email":"","orcid":"","institution":"Jiangsu Jiankang Vocational College","correspondingAuthor":false,"prefix":"","firstName":"Chan","middleName":"","lastName":"Wang","suffix":""},{"id":471910981,"identity":"cf6cedfa-f700-4e18-8fbc-228bf1810541","order_by":1,"name":"Jun zhou","email":"","orcid":"","institution":"Jiangsu Provinece (Suqian) 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Interaction","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cell-and-bioscience","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cbio","sideBox":"Learn more about [Cell \u0026 Bioscience](http://cellandbioscience.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/cbio/default.aspx","title":"Cell \u0026 Bioscience","twitterHandle":"@OACellBiology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Osteoarthritis, chondrocyte senescence, long non-coding RNA, HOXC-AS3, miR-615-3p, RRBP1, CIT, extracellular matrix, cellular homeostasis, RNA-protein interaction","lastPublishedDoi":"10.21203/rs.3.rs-6379719/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6379719/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eOsteoarthritis (OA) is a prevalent chronic joint disease characterized by progressive cartilage degeneration, significantly impairing quality of life for millions worldwide. Cellular senescence has emerged as a pivotal driver of OA pathogenesis, with senescent chondrocytes exhibiting a senescence-associated secretory phenotype that exacerbates tissue degradation. Long non-coding RNAs (lncRNAs) play critical roles in cartilage homeostasis, yet their regulatory mechanisms in OA remain incompletely understood. This study aimed to investigate the expression patterns, biological functions, and underlying mechanisms of lncRNA HOXC-AS3 in chondrocyte biology and OA pathogenesis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e LncRNA HOXC-AS3 was significantly downregulated in both OA cartilage tissues and IL-1β-treated human chondrocytes. Functional experiments demonstrated that HOXC-AS3 knockdown inhibited chondrocyte proliferation, promoted cellular senescence, and caused extracellular matrix imbalance, while its overexpression effectively reversed IL-1β-induced chondrocyte dysfunction. Mechanistic investigations revealed that HOXC-AS3 functions through dual molecular mechanisms: serving as a competing endogenous RNA by directly binding to miR-615-3p, and interacting with ribosome-binding protein 1 (RRBP1). Both mechanisms converged to regulate the expression of citron rho-interacting serine/threonine kinase (CIT), a key cell cycle regulator. Notably, CIT knockdown recapitulated the cellular phenotypes observed with HOXC-AS3 deficiency, while HOXC-AS3 overexpression rescued chondrocyte function by maintaining CIT expression levels even under inflammatory conditions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Our study identifies lncRNA HOXC-AS3 as a critical regulator of chondrocyte homeostasis that protects against OA progression through novel dual mechanisms: miR-615-3p sponging and RRBP1 interaction, both converging to maintain CIT expression. These findings not only enhance our understanding of the complex regulatory networks underlying OA pathogenesis but also highlight HOXCAS3 and its downstream effectors as potential therapeutic targets for OA treatment.\u003c/p\u003e","manuscriptTitle":"LncRNA HOXC-AS3 Prevents Chondrocyte Senescence and Osteoarthritis Progression Through miR-615-3p Sponging and RRBP1 Interaction","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-18 06:29:40","doi":"10.21203/rs.3.rs-6379719/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-08-01T08:47:24+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-16T10:50:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-07T10:42:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cell \u0026 Bioscience","date":"2025-04-05T04:08:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cell-and-bioscience","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cbio","sideBox":"Learn more about [Cell \u0026 Bioscience](http://cellandbioscience.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/cbio/default.aspx","title":"Cell \u0026 Bioscience","twitterHandle":"@OACellBiology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d414547e-5809-444c-8701-aee8de269806","owner":[],"postedDate":"June 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-16T16:05:50+00:00","versionOfRecord":{"articleIdentity":"rs-6379719","link":"https://doi.org/10.1186/s13578-026-01541-y","journal":{"identity":"cell-and-bioscience","isVorOnly":false,"title":"Cell \u0026 Bioscience"},"publishedOn":"2026-02-15 15:59:34","publishedOnDateReadable":"February 15th, 2026"},"versionCreatedAt":"2025-06-18 06:29:40","video":"","vorDoi":"10.1186/s13578-026-01541-y","vorDoiUrl":"https://doi.org/10.1186/s13578-026-01541-y","workflowStages":[]},"version":"v1","identity":"rs-6379719","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6379719","identity":"rs-6379719","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}