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Its initiation and progression are closely linked to immune dysregulation and chronic inflammation. Interleukin-33 (IL-33), a key member of the interleukin-1 cytokine family, was initially identified as an alarmin that promotes type 2 immune responses. However, accumulating evidence has demonstrated that IL-33 plays a complex and pivotal role in the regulation of bone homeostasis, making it a molecule of considerable interest in osteoimmunology. This review aims to systematically summarize the mechanisms by which the IL-33\/ST2 signaling axis regulates bone metabolism, further elucidate its multifaceted roles in primary and secondary osteoporosis, analyze its dual effects on bone protection and bone destruction, and evaluate its potential, as well as the associated challenges, as a diagnostic biomarker and therapeutic target.<\/jats:p>","DOI":"10.3390\/biom16060811","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:08:02Z","timestamp":1780535282000},"page":"811","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanisms of the IL-33\/ST2 Signaling Axis in Regulating Bone Metabolism"],"prefix":"10.3390","volume":"16","author":[{"given":"Libo","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou University, Lanzhou 730030, China"},{"name":"Orthopaedic Clinical Research Center of Gansu Province, Lanzhou 730030, China"},{"name":"Intelligent Orthopaedic Industry Technology Center of Gansu Province, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongcheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou University, Lanzhou 730030, China"},{"name":"Orthopaedic Clinical Research Center of Gansu Province, Lanzhou 730030, China"},{"name":"Intelligent Orthopaedic Industry Technology Center of Gansu Province, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zirui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou University, Lanzhou 730030, China"},{"name":"Orthopaedic Clinical Research Center of Gansu Province, Lanzhou 730030, China"},{"name":"Intelligent Orthopaedic Industry Technology Center of Gansu Province, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0654-0425","authenticated-orcid":false,"given":"Lei","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou University, Lanzhou 730030, China"},{"name":"Orthopaedic Clinical Research Center of Gansu Province, Lanzhou 730030, China"},{"name":"Intelligent Orthopaedic Industry Technology Center of Gansu Province, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou University, Lanzhou 730030, China"},{"name":"Orthopaedic Clinical Research Center of Gansu Province, Lanzhou 730030, China"},{"name":"Intelligent Orthopaedic Industry Technology Center of Gansu Province, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yayi","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou University, Lanzhou 730030, China"},{"name":"Orthopaedic Clinical Research Center of Gansu Province, Lanzhou 730030, China"},{"name":"Intelligent Orthopaedic Industry Technology Center of Gansu Province, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1001\/jama.2024.27154","article-title":"Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement","volume":"333","author":"Nicholson","year":"2025","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"731","DOI":"10.15585\/mmwr.mm7019a5","article-title":"QuickStats: Percentage* of Adults Aged \u226550 Years with Osteoporosis,(\u2020) by Race and Hispanic Origin(\u00a7)-United States, 2017\u20132018","volume":"70","author":"Wambogo","year":"2021","journal-title":"Morb. 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