GDF15 mediates inflammation-associated bone loss through a brain-bone axis

GDF15 mediates inflammation-associated bone loss through a brain-bone axis | 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 Biological Sciences - Article GDF15 mediates inflammation-associated bone loss through a brain-bone axis Dirk Elewaut, Renee Van der Cruyssen, Jan Devan, irina Heggli, and 28 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3824212/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Metabolic mediators play an important role in regulating inflammation(1). Rheumatoid arthritis and spondyloarthritis are common inflammatory diseases of the joint, aggravated in context of obesity(2). These patients experience systemic bone loss(3,4), which is not sufficiently controlled by disease-modifying therapeutics, despite adequate control of inflammation(5,6). Here we report an unexpected role for GDF15 (Growth Differentiation Factor 15), a central mediator of food intake(7–10), in inflammation-associated bone loss. Serum GDF15 levels were found to be elevated in arthritis patients and inversely correlated with bone density. However, GDF15 itself does not appear to promote arthritis. Rather, GDF15 mediates trabecular bone loss through its receptor GFRAL, which is expressed exclusively in the hindbrain(7–10). GDF15-GFRAL binding results in β-adrenergic activation of bone Marrow Adipogenic Lineage Precursors (MALPs), mesenchymal cells which are known to stimulate osteoclasts and trigger bone loss(11–14). These data demonstrate how a metabolic mediator controls bone loss through a brain-bone axis in inflammatory diseases. These findings may lead to more specific therapeutic interventions to protect bone through targeting GDF15 or MALPs. Biological sciences/Immunology/Osteoimmunology Biological sciences/Neuroscience/Peripheral nervous system/Autonomic nervous system Health sciences/Diseases/Immunological disorders/Inflammatory diseases Full Text Additional Declarations Yes there is potential Competing Interest. D.E. and S.L are inventors on patent WO2016050796A1. Supplementary Files Supplementarymethods.docx Supplementary methods Supplementarytables.docx Supplementary tables Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-3824212","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":268850609,"identity":"83f7a60d-67b9-4fd4-81a4-1577eabc4629","order_by":0,"name":"Dirk 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axis","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research 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Rheumatoid arthritis and spondyloarthritis are common inflammatory diseases of the joint, aggravated in context of obesity(2). These patients experience systemic bone loss(3,4), which is not sufficiently controlled by disease-modifying therapeutics, despite adequate control of inflammation(5,6). Here we report an unexpected role for GDF15 (Growth Differentiation Factor 15), a central mediator of food intake(7–10), in inflammation-associated bone loss. Serum GDF15 levels were found to be elevated in arthritis patients and inversely correlated with bone density. However, GDF15 itself does not appear to promote arthritis. Rather, GDF15 mediates trabecular bone loss through its receptor GFRAL, which is expressed exclusively in the hindbrain(7–10). GDF15-GFRAL binding results in β-adrenergic activation of bone Marrow Adipogenic Lineage Precursors (MALPs), mesenchymal cells which are known to stimulate osteoclasts and trigger bone loss(11–14). These data demonstrate how a metabolic mediator controls bone loss through a brain-bone axis in inflammatory diseases. These findings may lead to more specific therapeutic interventions to protect bone through targeting GDF15 or MALPs.","manuscriptTitle":"GDF15 mediates inflammation-associated bone loss through a brain-bone axis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-24 07:03:20","doi":"10.21203/rs.3.rs-3824212/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"36bc3796-c3d9-4833-b3c8-555e61b27594","owner":[],"postedDate":"January 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":28325754,"name":"Biological sciences/Immunology/Osteoimmunology"},{"id":28325755,"name":"Biological sciences/Neuroscience/Peripheral nervous system/Autonomic nervous system"},{"id":28325756,"name":"Health sciences/Diseases/Immunological disorders/Inflammatory diseases"}],"tags":[],"updatedAt":"2024-03-13T12:32:27+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-24 07:03:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3824212","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3824212","identity":"rs-3824212","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}