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Journal of Translational Medicine

Journal of Translational Medicine

IF: 6.1
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The integrin α2-osteoclast axis: a key driver of bone destruction and therapeutic target in osteosarcoma

Published:31 October 2025 DOI: 10.1186/s12967-025-06906-4 PMID: 41174632
Hongxiang Wei,?Kai Shi,?Daoxiang Huang,?Huangfeng Lin,?Shenglin Wang,?Xuanwei Chen,?Wenming Zhang

Abstract

Background: Osteosarcoma is an aggressive bone malignancy with elusive core driving mechanisms. Dysregulated expression of integrin α2 (ITGA2) promotes malignant progression in multiple cancers, yet its role in osteosarcoma and correlation with bone destruction remain poorly understood. This study investigated the potential role of ITGA2 in osteosarcoma progression and therapeutic targeting.

Methods: Integrating bioinformatics analysis and experimental validation, we explored ITGA2 dysregulation and its clinical significance in osteosarcoma. Public databases were analyzed to confirm ITGA2 overexpression. CCK-8 assay, colony formation, Transwell migration/invasion assays, wound healing, and cell transcriptomics were employed to assess ITGA2's impact on tumor proliferation, migration, and invasion. Xenograft mouse models evaluated ITGA2-driven tumor growth and osteolytic damage. WB analyzed ITGA2-mediated modulation of osteoclast differentiation-related molecules (RANKL, MMP9, OPN). ITGA2 knockdown and inhibitor (E7820) intervention were applied, with Western Blot (WB)/ Immunohistochemistry (IHC) validating ITGA2-MMP9 interactions.

Results: Clinical cohorts and bioinformatics revealed ITGA2-specific overexpression in osteosarcoma tissues/cells (P?

Conclusion: This study uncovered that ITGA2 drives osteosarcoma progression and aggravates osteolysis via the "ITGA2-osteoclast axis", with high expression predicting poor outcomes. Mechanistically, ITGA2 promoted tumor invasion and bone metabolism imbalance by regulating osteoclastogenic signaling, while its targeted inhibition synergistically suppresses tumor growth and restores bone homeostasis, highlighting ITGA2 as a pivotal therapeutic target for osteosarcoma.

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