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While testosterone (Tes) is considered to be possibly protective, its regulatory mechanism in bone remodeling remains unclear. Here, bone microarchitectural analysis indicates that elderly men exhibit reduced cortical and trabecular thickness with elevated cortical porosity, particularly at the superior femoral head near the medial acetabulum. Serum profiling of 352 individuals showed that low Tes levels (&lt;9.415 nmol\u00b7L<jats:sup>\u22121<\/jats:sup>) are associated with higher risk of bone loss. In vivo, tail\u2010suspended mice lacking osteoblastic androgen receptor (AR) displayed similar femoral deterioration, with decreased trabecular bone and increased cortical porosity. Mechanistically, Tes enhances osteoblastic differentiation via AR\u2010mediated upregulation of tenascin\u2010C (TNC). Molecular docking suggests the fibrinogen C\u2010terminal domain of TNC inhibits osteoclastogenesis by binding integrin \u03b1V, blocking adhesion of RGD\u2010containing proteins. A synthetic peptide (pep2) mimicking this domain preserved bone architecture in osteoblast\u2010specific <jats:italic>Ar<\/jats:italic>\u2010knockout, tail\u2010suspended mice. Moreover, elevated serum extracellular vesicle amyloid precursor protein, secondary to Tes\u2010AR\u2010TNC decline and osteoclast overactivation, emerged as a biomarker of bone loss when combined with low Tes. This study identifies the Tes\u2010AR\u2010TNC axis as a key regulator of male bone remodeling, offering insights into fracture risk assessment and targeted interventions in bone destruction.<\/jats:p>","DOI":"10.1002\/advs.202501518","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T05:39:06Z","timestamp":1748583546000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Testosterone Delays Bone Microstructural Destruction via Osteoblast\u2010Androgen Receptor\u2010Mediated Upregulation of Tenascin\u2010C"],"prefix":"10.1002","volume":"12","author":[{"given":"Yong","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Fourth Medical Center Chinese PLA General Hospital  Beijing 100048 China"},{"name":"State Key Laboratory of Complex, Severe, and Rare Diseases Department of Immunology Institute of Basic Medical Sciences Chinese Academy of Medical 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