{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T06:05:53Z","timestamp":1784786753615,"version":"3.55.0"},"reference-count":186,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Ankylosing spondylitis (AS) is a chronic, immune-mediated disease characterized by inflammatory arthritis and pathological new bone formation, ultimately leading to spinal fusion and functional impairment. Despite effective suppression of inflammation by biologic agents targeting cytokines such as TNF-\u03b1 and IL-17A, radiographic progression often continues, highlighting a critical dissociation between inflammatory activity and structural damage. The literature suggests that macrophage polarization and the TGF-\u03b2\/BMP signaling axis collectively constitute a critical nexus linking inflammation to aberrant osteogenesis in AS. Moreover, it details how the unique entheseal microenvironment\u2014shaped by biomechanical stress, hypoxia, and a distinct cytokine milieu\u2014drives macrophages toward a spectrum of pro-osteogenic phenotypes through a mechano-inflammatory feedback loop. After that, polarized macrophages, in turn, serve as pivotal cellular engineers that locally activate and sustain TGF-\u03b2\/BMP signals through proteolytic cleavage and acidic remodeling of the ECM. This self-amplifying loop directly orchestrates endochondral ossification at ligamentous insertion sites, culminating in syndesmophyte formation and spinal ankylosis. Therapeutically, this mechanistic understanding highlights promising avenues for disease modification beyond conventional anti-inflammatory strategies. Targeting macrophage polarization states or disrupting the TGF-\u03b2\/BMP activation cascade may offer dual benefits\u2014suppressing both inflammation and structural progression\u2014and pave the way for genuine disease-modifying therapies in AS.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1788883","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T05:38:28Z","timestamp":1784785108000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting macrophage-mediated TGF-\u03b2\/BMP signaling in ankylosing spondylitis: from inflammation to pathological bone formation"],"prefix":"10.3389","volume":"17","author":[{"given":"Shalayiding","family":"Aierxiding","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Xinjiang 474 hospital","place":["\u00dcr\u00fcmqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery I, The Sixth Affiliated Hospital of Xinjiang Medical University","place":["\u00dcr\u00fcmqi, Xinjiang, China"]},{"name":"Xinjiang Institute of Spinal Surgery, The Sixth Affiliated Hospital of Xinjiang Medical University","place":["\u00dcr\u00fcmqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)02263-3","article-title":"Axial spondyloarthritis","volume":"405","author":"Navarro-Comp\u00e1n","year":"2025","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ard.2025.09.016","article-title":"Understanding the drivers of BASDAI and back pain scores in psoriatic arthritis","volume":"85","author":"Mehta","year":"2026","journal-title":"Ann Rheum Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14113677","article-title":"The genetic background of ankylosing spondylitis reveals a distinct overlap with autoimmune diseases: a systematic review","volume":"14","author":"Zormpa","year":"2025","journal-title":"J Clin Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60635-7","article-title":"Ankylosing spondylitis","volume":"369","author":"Braun","year":"2007","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1406182","article-title":"Ankylosing spondylitis and axial spondyloarthritis","volume":"374","author":"Taurog","year":"2016","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2667","article-title":"Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci","volume":"45","author":"Cortes","year":"2013","journal-title":"Nat Genet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2018.07.007","article-title":"Evolving concepts of new bone formation in axial spondyloarthritis: insights from animal models and human studies","volume":"31","author":"Lories","year":"2017","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keaa807","article-title":"Diagnostic delay in axial spondyloarthritis: a systematic review and meta-analysis","volume":"60","author":"Zhao","year":"2021","journal-title":"Rheumatol (Oxford)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2014.10.004","article-title":"Disease activity measurements and monitoring in psoriatic arthritis and axial spondyloarthritis","volume":"28","author":"MaChado","year":"2014","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab523","article-title":"New developments in ankylosing spondylitis-status in 2021","volume":"60","author":"Klavdianou","year":"2021","journal-title":"Rheumatol (Oxford)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-022-00761-z","article-title":"Treatment of axial spondyloarthritis: an update","volume":"18","author":"Danve","year":"2022","journal-title":"Nat Rev Rheumatol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/art.40786","article-title":"Progression of structural damage in the sacroiliac joints in patients with early axial spondyloarthritis during long-term anti-tumor necrosis factor treatment: six-year results of continuous treatment with etanercept","volume":"71","author":"Rios Rodriguez","year":"2019","journal-title":"Arthritis Rheumatol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ard.2025.03.017","article-title":"Radiographic structural damage in axial spondyloarthritis: is there a preferred way to quantify progression over time? 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