Yong Xie, Meng Pan, Zeyuan Zhang, Licheng Zhang, Haotian Liu, Xia Wang, William W Lu, Peifu Tang, Wei Ge
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In vivo, tail-suspended 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-mediated upregulation of tenascin-C (TNC). Molecular docking suggests the fibrinogen C-terminal domain of TNC inhibits osteoclastogenesis by binding integrin αV, blocking adhesion of RGD-containing proteins. A synthetic peptide (pep2) mimicking this domain preserved bone architecture in osteoblast-specific <i>Ar</i>-knockout, tail-suspended mice. Moreover, elevated serum extracellular vesicle amyloid precursor protein, secondary to Tes-AR-TNC decline and osteoclast overactivation, emerged as a biomarker of bone loss when combined with low Tes. 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引用次数: 0
摘要
老年男性骨质流失和微结构破坏与骨折和高死亡率有关。虽然睾酮(Tes)被认为可能具有保护作用,但其在骨重塑中的调节机制尚不清楚。此处,骨微结构分析表明,老年男性表现为皮质和小梁厚度减少,皮质孔隙率升高,特别是在靠近髋臼内侧的股骨头上。352人的血清分析显示,低Tes水平(-1)与骨质流失的高风险相关。在体内,缺乏成骨雄激素受体(AR)的尾悬小鼠表现出类似的股骨退化,小梁骨减少,皮质孔隙度增加。从机制上讲,Tes通过ar介导的tenascin-C (TNC)上调来增强成骨细胞分化。分子对接提示TNC的纤维蛋白原c端结构域通过结合整合素αV抑制破骨细胞生成,阻断含rgd蛋白的粘附。模拟该结构域的合成肽(pep2)在成骨细胞特异性ar敲除的尾悬小鼠中保存了骨结构。此外,血清细胞外囊泡淀粉样前体蛋白升高,继发于Tes- ar - tnc下降和破骨细胞过度活化,当与低Tes结合时,成为骨质流失的生物标志物。本研究确定了Tes-AR-TNC轴是男性骨重塑的关键调节因子,为骨折风险评估和骨破坏的针对性干预提供了见解。
Testosterone Delays Bone Microstructural Destruction via Osteoblast-Androgen Receptor-Mediated Upregulation of Tenascin-C
Bone loss and microstructural destruction in elderly men are associated with fractures and high mortality. 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 (<9.415 nmol·L−1) are associated with higher risk of bone loss. In vivo, tail-suspended 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-mediated upregulation of tenascin-C (TNC). Molecular docking suggests the fibrinogen C-terminal domain of TNC inhibits osteoclastogenesis by binding integrin αV, blocking adhesion of RGD-containing proteins. A synthetic peptide (pep2) mimicking this domain preserved bone architecture in osteoblast-specific Ar-knockout, tail-suspended mice. Moreover, elevated serum extracellular vesicle amyloid precursor protein, secondary to Tes-AR-TNC decline and osteoclast overactivation, emerged as a biomarker of bone loss when combined with low Tes. This study identifies the Tes-AR-TNC axis as a key regulator of male bone remodeling, offering insights into fracture risk assessment and targeted interventions in bone destruction.
期刊介绍:
Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.