MSC polarization in the microenvironment promotes pathological new bone formation in inflammatory lesions

MSC polarization in the microenvironment promotes pathological new bone formation in inflammatory lesions | 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 MSC polarization in the microenvironment promotes pathological new bone formation in inflammatory lesions Tao He, Xin Huang, Guanghao Chi, Xinli Zhou, Youcun Qian, Yuxin Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7508709/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Chronic inflammatory diseases such as ankylosing spondylitis (AS) are characterised by pathological new bone formation (NBF); however, the underlying mechanisms are not well understood. This study investigates the role of mesenchymal stromal cell (MSC) polarization in promoting NBF in the inflammatory microenvironment of AS. Using in vitro and in vivo models, we demonstrate that high levels of interleukin-17 (IL-17) induce the polarization of Toll-like receptor 3-positive (TLR3+) MSC2, driving osteogenic differentiation via the WNT10b pathway. In contrast, low IL-17 levels promote the polarization of TLR4+MSC1, thereby enhancing pro-inflammatory responses. In a decorin-induced mouse model of AS, the implantation of TLR3+MSC2 suppressed local inflammation and promoted NBF. However, TLR3 knockout attenuated these effects. RNA sequencing and functional assays in peripheral blood mononuclear cells (PBMCs) confirmed an association between TLR3+MSC2 polarization and Wnt pathway activation in AS patients with NBF. Furthermore, treatment with TLR4+MSC1 or Wnt inhibitors restored the balance of inflammation and immunity, effectively suppressing pathological NBF. These findings reveal that IL-17-dependent MSC polarization plays a crucial role in regulating the transition from inflammation to NBF in AS via the TLR3/WNT10b axis. This provides new insights into targeted therapies for chronic inflammatory and proliferative disorders. Health sciences/Medical research/Stem-cell research Biological sciences/Stem cells/Mesenchymal stem cells Health sciences/Diseases/Rheumatic diseases/Spondyloarthritis/Ankylosing spondylitis mesenchymal stem cells polarization Toll-like receptor signaling ankylosing spondylitis new bone formation interleukin-17 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTable2.docx Supplementary Table 2 SupplementaryTable1.docx Supplementary Table 1 SupplementaryVideo1.avi WT mice. SupplementaryVideo6.avi A DCN/TLR4+MSC-treated Il17a-GFP mouse. SupplementaryVideo2.avi DCN-treated Il17a-GFP mice. SupplementaryVideo5.avi DCN/GFP+IL23/TLR3+MSC-treated Il17a-/- mice. SupplementaryVideo4.avi IL17-treated Tlr3-/- mice. SupplementaryVideo3.avi DCN/GFP+IL23-treated Il17a-/- mice. Cite Share Download PDF Status: Under Review 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-7508709","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":515845060,"identity":"c84a36f8-de22-4c9d-ad06-b0b5d839535e","order_by":0,"name":"Tao 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This study investigates the role of mesenchymal stromal cell (MSC) polarization in promoting NBF in the inflammatory microenvironment of AS. Using in vitro and in vivo models, we demonstrate that high levels of interleukin-17 (IL-17) induce the polarization of Toll-like receptor 3-positive (TLR3+) MSC2, driving osteogenic differentiation via the WNT10b pathway. In contrast, low IL-17 levels promote the polarization of TLR4+MSC1, thereby enhancing pro-inflammatory responses. In a decorin-induced mouse model of AS, the implantation of TLR3+MSC2 suppressed local inflammation and promoted NBF. However, TLR3 knockout attenuated these effects. RNA sequencing and functional assays in peripheral blood mononuclear cells (PBMCs) confirmed an association between TLR3+MSC2 polarization and Wnt pathway activation in AS patients with NBF. Furthermore, treatment with TLR4+MSC1 or Wnt inhibitors restored the balance of inflammation and immunity, effectively suppressing pathological NBF. 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